KR101945162B1 - A method of screening a medicine for treating or preventing filariasis - Google Patents
A method of screening a medicine for treating or preventing filariasis Download PDFInfo
- Publication number
- KR101945162B1 KR101945162B1 KR1020180142930A KR20180142930A KR101945162B1 KR 101945162 B1 KR101945162 B1 KR 101945162B1 KR 1020180142930 A KR1020180142930 A KR 1020180142930A KR 20180142930 A KR20180142930 A KR 20180142930A KR 101945162 B1 KR101945162 B1 KR 101945162B1
- Authority
- KR
- South Korea
- Prior art keywords
- calumenin
- screening
- filariasis
- treating
- ligand
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000012216 screening Methods 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 title abstract description 17
- 201000006353 Filariasis Diseases 0.000 title abstract description 13
- 101710191075 Calumenin Proteins 0.000 claims abstract description 73
- 102100021848 Calumenin Human genes 0.000 claims abstract description 73
- 239000003446 ligand Substances 0.000 claims abstract description 25
- 241000282414 Homo sapiens Species 0.000 claims abstract description 13
- 238000004590 computer program Methods 0.000 claims abstract description 8
- 238000003032 molecular docking Methods 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 12
- 244000052769 pathogen Species 0.000 claims description 8
- 230000001717 pathogenic effect Effects 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 3
- 229910052686 Californium Inorganic materials 0.000 claims description 2
- HGLDOAKPQXAFKI-UHFFFAOYSA-N californium atom Chemical compound [Cf] HGLDOAKPQXAFKI-UHFFFAOYSA-N 0.000 claims description 2
- 230000003449 preventive effect Effects 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 7
- 241000243985 Onchocerca volvulus Species 0.000 description 38
- 241000244206 Nematoda Species 0.000 description 32
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 27
- 229960004130 itraconazole Drugs 0.000 description 27
- 208000002042 onchocerciasis Diseases 0.000 description 25
- 238000002474 experimental method Methods 0.000 description 21
- 108090000623 proteins and genes Proteins 0.000 description 15
- 229940079593 drug Drugs 0.000 description 14
- 102000004169 proteins and genes Human genes 0.000 description 14
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 description 12
- HXHWSAZORRCQMX-UHFFFAOYSA-N albendazole Chemical compound CCCSC1=CC=C2NC(NC(=O)OC)=NC2=C1 HXHWSAZORRCQMX-UHFFFAOYSA-N 0.000 description 12
- 229960002669 albendazole Drugs 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 12
- 101000898068 Homo sapiens Calumenin Proteins 0.000 description 11
- 102000056489 human CALU Human genes 0.000 description 11
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 description 10
- 229960002418 ivermectin Drugs 0.000 description 10
- 241000244038 Brugia malayi Species 0.000 description 9
- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 description 8
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 8
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 8
- 125000003275 alpha amino acid group Chemical group 0.000 description 8
- 229960000908 idarubicin Drugs 0.000 description 8
- 229960001057 paliperidone Drugs 0.000 description 8
- 244000045947 parasite Species 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- 241000238631 Hexapoda Species 0.000 description 6
- 229930182558 Sterol Natural products 0.000 description 6
- 150000003432 sterols Chemical class 0.000 description 6
- 235000003702 sterols Nutrition 0.000 description 6
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 description 5
- 229960003974 diethylcarbamazine Drugs 0.000 description 5
- RCKMWOKWVGPNJF-UHFFFAOYSA-N diethylcarbamazine Chemical compound CCN(CC)C(=O)N1CCN(C)CC1 RCKMWOKWVGPNJF-UHFFFAOYSA-N 0.000 description 5
- 239000002547 new drug Substances 0.000 description 5
- IKQRPFTXKQQLJF-IAHYZSEUSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-n-(pyrrolidin-1-ylmethyl)-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound OC([C@@]1(O)C(=O)C=2[C@@H]([C@](C3=CC=CC(O)=C3C=2O)(C)O)C[C@H]1[C@@H](C1=O)N(C)C)=C1C(=O)NCN1CCCC1 IKQRPFTXKQQLJF-IAHYZSEUSA-N 0.000 description 4
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 229960000975 daunorubicin Drugs 0.000 description 4
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 4
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 241000607479 Yersinia pestis Species 0.000 description 3
- NWGGKKGAFZIVBJ-UHFFFAOYSA-N antrafenine Chemical compound FC(F)(F)C1=CC=CC(N2CCN(CCOC(=O)C=3C(=CC=CC=3)NC=3C4=CC=C(C=C4N=CC=3)C(F)(F)F)CC2)=C1 NWGGKKGAFZIVBJ-UHFFFAOYSA-N 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 208000003177 ocular onchocerciasis Diseases 0.000 description 3
- 230000003071 parasitic effect Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 244000291564 Allium cepa Species 0.000 description 2
- 235000002732 Allium cepa var. cepa Nutrition 0.000 description 2
- 101100518633 Caenorhabditis elegans dpy-18 gene Proteins 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 241000255925 Diptera Species 0.000 description 2
- 206010016675 Filariasis lymphatic Diseases 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- 208000037263 Lymphatic filariasis Diseases 0.000 description 2
- 230000006819 RNA synthesis Effects 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000244005 Wuchereria bancrofti Species 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- IKENVDNFQMCRTR-UHFFFAOYSA-N conivaptan Chemical compound C12=CC=CC=C2C=2NC(C)=NC=2CCN1C(=O)C(C=C1)=CC=C1NC(=O)C1=CC=CC=C1C1=CC=CC=C1 IKENVDNFQMCRTR-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000000442 dopamine 2 receptor blocking agent Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 239000003596 drug target Substances 0.000 description 2
- XCGSFFUVFURLIX-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C=3C=CC=C4NC=C(C=34)C2)=C1)C)C1=CC=CC=C1 XCGSFFUVFURLIX-VFGNJEKYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 208000005239 filarial elephantiasis Diseases 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229960005009 rolitetracycline Drugs 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000002864 sequence alignment Methods 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- QMGVPVSNSZLJIA-FVWCLLPLSA-N strychnine Chemical compound O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-N 0.000 description 2
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000003041 virtual screening Methods 0.000 description 2
- BQPPJGMMIYJVBR-UHFFFAOYSA-N (10S)-3c-Acetoxy-4.4.10r.13c.14t-pentamethyl-17c-((R)-1.5-dimethyl-hexen-(4)-yl)-(5tH)-Delta8-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products CC12CCC(OC(C)=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C BQPPJGMMIYJVBR-UHFFFAOYSA-N 0.000 description 1
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- CHGIKSSZNBCNDW-UHFFFAOYSA-N (3beta,5alpha)-4,4-Dimethylcholesta-8,24-dien-3-ol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21 CHGIKSSZNBCNDW-UHFFFAOYSA-N 0.000 description 1
- XYTLYKGXLMKYMV-UHFFFAOYSA-N 14alpha-methylzymosterol Natural products CC12CCC(O)CC1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C XYTLYKGXLMKYMV-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- AZSNMRSAGSSBNP-XPNPUAGNSA-N 22,23-dihydroavermectin B1a Chemical compound C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 AZSNMRSAGSSBNP-XPNPUAGNSA-N 0.000 description 1
- FPTJELQXIUUCEY-UHFFFAOYSA-N 3beta-Hydroxy-lanostan Natural products C1CC2C(C)(C)C(O)CCC2(C)C2C1C1(C)CCC(C(C)CCCC(C)C)C1(C)CC2 FPTJELQXIUUCEY-UHFFFAOYSA-N 0.000 description 1
- -1 4-hydroxy-3,5-dimethoxyphenyl Chemical group 0.000 description 1
- 102000056834 5-HT2 Serotonin Receptors Human genes 0.000 description 1
- 108091005479 5-HT2 receptors Proteins 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
- 241000256111 Aedes <genus> Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000256186 Anopheles <genus> Species 0.000 description 1
- 241001156002 Anthonomus pomorum Species 0.000 description 1
- UYIFTLBWAOGQBI-BZDYCCQFSA-N Benzhormovarine Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4O)C)CC2=CC=3OC(=O)C1=CC=CC=C1 UYIFTLBWAOGQBI-BZDYCCQFSA-N 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 241000143302 Brugia timori Species 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- 101150052163 CALU gene Proteins 0.000 description 1
- 241000244202 Caenorhabditis Species 0.000 description 1
- 102000005701 Calcium-Binding Proteins Human genes 0.000 description 1
- 108010045403 Calcium-Binding Proteins Proteins 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 description 1
- 241000256054 Culex <genus> Species 0.000 description 1
- 241000254171 Curculionidae Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 229940123603 Dopamine D2 receptor antagonist Drugs 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 229940124602 FDA-approved drug Drugs 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- BKLIAINBCQPSOV-UHFFFAOYSA-N Gluanol Natural products CC(C)CC=CC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(O)C(C)(C)C4CC3 BKLIAINBCQPSOV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- LOPKHWOTGJIQLC-UHFFFAOYSA-N Lanosterol Natural products CC(CCC=C(C)C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 LOPKHWOTGJIQLC-UHFFFAOYSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 208000008771 Lymphadenopathy Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- JFXBEKISTKFVAB-AJQTZOPKSA-N Metocurine Chemical compound C1([C@@H]([N+](CCC1=CC=1OC)(C)C)CC2=CC=C(C=C2)O2)=CC=1OC(=C1)C(OC)=CC=C1C[C@H]1[N+](C)(C)CCC3=C1C2=C(OC)C(OC)=C3 JFXBEKISTKFVAB-AJQTZOPKSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 102000005431 Molecular Chaperones Human genes 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- CAHGCLMLTWQZNJ-UHFFFAOYSA-N Nerifoliol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C CAHGCLMLTWQZNJ-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- QMGVPVSNSZLJIA-UHFFFAOYSA-N Nux Vomica Natural products C1C2C3C4N(C=5C6=CC=CC=5)C(=O)CC3OCC=C2CN2C1C46CC2 QMGVPVSNSZLJIA-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 102000004079 Prolyl Hydroxylases Human genes 0.000 description 1
- 108010043005 Prolyl Hydroxylases Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 241000256108 Simulium <genus> Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 102000017168 Sterol 14-Demethylase Human genes 0.000 description 1
- 108010013803 Sterol 14-Demethylase Proteins 0.000 description 1
- 241001468227 Streptomyces avermitilis Species 0.000 description 1
- 241001279009 Strychnos toxifera Species 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 101000930762 Sulfolobus acidocaldarius (strain ATCC 33909 / DSM 639 / JCM 8929 / NBRC 15157 / NCIMB 11770) Signal recognition particle receptor FtsY Proteins 0.000 description 1
- 241000242541 Trematoda Species 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 229950004064 antrafenine Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 description 1
- 229960004754 astemizole Drugs 0.000 description 1
- RRZXIRBKKLTSOM-XPNPUAGNSA-N avermectin B1a Chemical class C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 RRZXIRBKKLTSOM-XPNPUAGNSA-N 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 229960003340 calcium silicate Drugs 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229930188550 carminomycin Natural products 0.000 description 1
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229950001725 carubicin Drugs 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229960003728 ciclesonide Drugs 0.000 description 1
- 230000036570 collagen biosynthesis Effects 0.000 description 1
- 238000005094 computer simulation Methods 0.000 description 1
- 229960000562 conivaptan Drugs 0.000 description 1
- 230000034334 cuticle development Effects 0.000 description 1
- POZRVZJJTULAOH-LHZXLZLDSA-N danazol Chemical compound C1[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=CC2=C1C=NO2 POZRVZJJTULAOH-LHZXLZLDSA-N 0.000 description 1
- 229960000766 danazol Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- QBSJHOGDIUQWTH-UHFFFAOYSA-N dihydrolanosterol Natural products CC(C)CCCC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 QBSJHOGDIUQWTH-UHFFFAOYSA-N 0.000 description 1
- METQSPRSQINEEU-UHFFFAOYSA-N dihydrospirorenone Natural products CC12CCC(C3(CCC(=O)C=C3C3CC33)C)C3C1C1CC1C21CCC(=O)O1 METQSPRSQINEEU-UHFFFAOYSA-N 0.000 description 1
- 229940047564 dimethyltubocurarine Drugs 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- METQSPRSQINEEU-HXCATZOESA-N drospirenone Chemical compound C([C@]12[C@H]3C[C@H]3[C@H]3[C@H]4[C@@H]([C@]5(CCC(=O)C=C5[C@@H]5C[C@@H]54)C)CC[C@@]31C)CC(=O)O2 METQSPRSQINEEU-HXCATZOESA-N 0.000 description 1
- 229960004845 drospirenone Drugs 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 229960004199 dutasteride Drugs 0.000 description 1
- JWJOTENAMICLJG-QWBYCMEYSA-N dutasteride Chemical compound O=C([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)N[C@@H]4CC3)C)CC[C@@]21C)NC1=CC(C(F)(F)F)=CC=C1C(F)(F)F JWJOTENAMICLJG-QWBYCMEYSA-N 0.000 description 1
- 150000002061 ecdysteroids Chemical class 0.000 description 1
- 208000006036 elephantiasis Diseases 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 229960001208 eplerenone Drugs 0.000 description 1
- JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
- 229960004943 ergotamine Drugs 0.000 description 1
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 description 1
- 229950002007 estradiol benzoate Drugs 0.000 description 1
- 229940012028 ethynodiol diacetate Drugs 0.000 description 1
- ONKUMRGIYFNPJW-KIEAKMPYSA-N ethynodiol diacetate Chemical compound C1C[C@]2(C)[C@@](C#C)(OC(C)=O)CC[C@H]2[C@@H]2CCC3=C[C@@H](OC(=O)C)CC[C@@H]3[C@H]21 ONKUMRGIYFNPJW-KIEAKMPYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229960004500 flubendazole Drugs 0.000 description 1
- CPEUVMUXAHMANV-UHFFFAOYSA-N flubendazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=C(F)C=C1 CPEUVMUXAHMANV-UHFFFAOYSA-N 0.000 description 1
- 229940042902 flumethasone pivalate Drugs 0.000 description 1
- JWRMHDSINXPDHB-OJAGFMMFSA-N flumethasone pivalate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)COC(=O)C(C)(C)C)(O)[C@@]2(C)C[C@@H]1O JWRMHDSINXPDHB-OJAGFMMFSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 210000004349 growth plate Anatomy 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- CAHGCLMLTWQZNJ-RGEKOYMOSA-N lanosterol Chemical compound C([C@]12C)C[C@@H](O)C(C)(C)[C@H]1CCC1=C2CC[C@]2(C)[C@H]([C@H](CCC=C(C)C)C)CC[C@@]21C CAHGCLMLTWQZNJ-RGEKOYMOSA-N 0.000 description 1
- 229940058690 lanosterol Drugs 0.000 description 1
- 238000009630 liquid culture Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 208000018555 lymphatic system disease Diseases 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 208000004141 microcephaly Diseases 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 238000002887 multiple sequence alignment Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- 150000007523 nucleic acids Chemical group 0.000 description 1
- 239000002773 nucleotide Chemical group 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000034958 pharyngeal pumping Effects 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000000455 protein structure prediction Methods 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000037380 skin damage Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960005453 strychnine Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 208000037972 tropical disease Diseases 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2570/00—Omics, e.g. proteomics, glycomics or lipidomics; Methods of analysis focusing on the entire complement of classes of biological molecules or subsets thereof, i.e. focusing on proteomes, glycomes or lipidomes
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Physics & Mathematics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Biophysics (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Bioinformatics & Computational Biology (AREA)
- Biotechnology (AREA)
- Evolutionary Biology (AREA)
- Medical Informatics (AREA)
- Theoretical Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
본 발명은 사상충증(filariasis) 치료용 또는 예방용 약학적 조성물 및 이의 스크리닝 방법에 관한 것으로서, 보다 구체적으로 사상충의 calumenin에 특이적으로 결합하는 사상충증 치료용 약물을 포함하는 약학적 조성물 및 이를 컴퓨터 프로그램을 통하여 스크리닝 하는 방법에 관한 것이다.The present invention relates to a pharmaceutical composition for treating or preventing filariasis and a method for screening the composition, and more particularly, to a pharmaceutical composition comprising a drug for treating onchocerciasis which specifically binds to calumenin of a willowworm, Lt; / RTI >
림프사상충증(Lymphatic filariasis) 및 회선사상충증(Onchocerciasis)은 사상충 선충에 의해 감염되는 주요 열대성 질병이다. 림프사상충증은 모기를 매개로 하여(Culex, Anopheles and Aedes spp.) 전염되며, 전세계 54개국의 9억 7,400만명이 이 질병으로 위협 받는다(Cobo, 2016). 반크롭트 사상충(Wuchereria bancrofti), 말레이사상충(Brugia malayi) 및 티몰사상충(Brugia timori)이 림프사상충증의 주요 원인이 된다Lymphatic filariasis and onchocerciasis are the major tropical diseases infected by the wasp nematode. Onchocerciasis is transmitted via mosquitoes (Culex, Anopheles and Aedes spp.), And 974 million people in 54 countries are threatened with this disease (Cobo, 2016). Wuchereria bancrofti, Brugia malayi and Brugia timori are the main causes of onchocerciasis of the lymphatic system
림프사상충증이 만성화되면, 사지(四肢)의 림프 부종(조직 부종) 또는 피부 조직이 응축되는 코끼리증(elephantiasis)이 발병할 수 있다. 회선사상충(Onchocerca volvulus)에 의한 회선사상충증(onchocerciasis=river blindness)은 먹파리(Simulium spp.)에 의해 사하라 사막 이남의 아프리카 31개국, 라틴 아메리카 3개국, 예멘에서 전파된다(WHO, 2016). 만성 감염은 가려움증과 피부 손상을 초래하고 영구적 실명이 발생할 수 있는 안구 질병을 유발한다. Chlamydia inlithiasis can result in limb swelling of the extremities (edema of the tissue) or elephantiasis in which the skin tissue condenses. Onchocerciasis = river blindness caused by onchocerca volvulus is spread in 31 African sub-Saharan Africa, three Latin American countries, and Yemen (WHO, 2016) by Simulium spp. Chronic infections lead to itching and skin damage and eye diseases that can lead to permanent blindness.
이러한 인간의 사상충증에 대한 치료 방법에는 매개체의 제어 및 집단 약물 투여(massive drug administration, MDA)가 있다. 그러나 수많은 노력에도 불구하고, 질병의 통제와 치료는 백신의 부재 또는 집단 약물 투여(MDA)에 사용되는 약물의 제한적인 효과 때문에 성공하지 못했다. 현재 다이에틸카바마진(Diethylcarbamazine, DEC), 알벤다졸(Albendazole, ALB) 및 이버멕틴(Ivermectin, IVM)이 집단 약물 투여 방법에서 사용된다(Hoerauf, 2008). 림프사상충증에는 다이에틸카바마진, 알벤다졸, 이버멕틴 중 두 가지 약물의 병행 투여가 가능하지만, 회선사상충증의 치료 약물은 이버멕틴이 유일하여, 약물에 대한 내성이 발생하는 문제가 있다(Cobo, 2016; Cupp et al., 2011). Methods for treating such onchocerciasis include mediator control and massive drug administration (MDA). Despite numerous efforts, however, control and treatment of the disease has not been successful due to the absence of a vaccine or the limited effect of drugs used in group drug administration (MDA). Currently, diethylcarbamazine (DEC), albendazole (ALB), and Ivermectin (IVM) are used in group drug administration methods (Hoerauf, 2008). In addition, two drugs, diethylcarbamazine, albendazole and ivermectin, can be administered concurrently with onchocerciasis due to lymphadenopathy. However, ivermectin is the only treatment drug for onchocerciasis, and resistance to drugs is generated (Cobo, Cupp et al., 2011).
상기의 문제점을 해결하기 위해서 새로운 분자를 표적으로 하는 신약의 개발이 필요하다. 신약은 성충 사상충의 살충 효과가 우수하거나, 성충 사상충에 대한 불임 효과가 장기적이어야 하며, 기생충 살충으로 인한 심각한 부작용이 없어야 한다. 또한, 어린이, 임신여성 및 모유 수유 여성에게 안전해야 한다. In order to solve the above problems, it is necessary to develop a new drug targeting a new molecule. New drugs should have a good insecticidal effect on adult insect pests, have a long-term effect on insect pests, and have no serious side effects from parasite insects. It should also be safe for children, pregnant women and breastfeeding women.
선충의 큐티클은 외부로부터의 약물 전달에 깊이 관여하기 때문에, 돌연변이의 큐티클 결함은 신약 개발과 관련하여 매우 의미있다(Fetterer and Rhoads, 1993; Geary et al., 1995; Ho et al., 1990; Sheehy et al. , 2000, Thompson et al., 1993). 더욱, 콜라겐으로 구성된 세포 외 매트릭스인 선충의 큐티클은 선충의 발달과 생존에 중요하다. 따라서 큐티클 발달과 관련된 많은 효소와 샤페론(chaperones)이 기생 선충의 잠재적 약물 표적으로 제안되었다(Frand et al., 2005; Page et al., 2014).Since cuticle nematodes are deeply involved in drug delivery from the outside, mutation cuticle defects are highly relevant for drug development (Fetterer and Rhoads, 1993; Geary et al., 1995; Ho et al., 1990; Sheehy et al., 2000, Thompson et al., 1993). Furthermore, the cuticle of the nematode, an extracellular matrix composed of collagen, is important for nematode development and survival. Thus, many enzymes and chaperones associated with cuticle development have been proposed as potential drug targets for parasitic nematodes (Frand et al., 2005; Page et al., 2014).
최근에 단백질 구조를 예측하는 컴퓨터 알고리즘이 발전하여, 아미노산 서열로부터 목적 단백질의 3차원(3D) 구조를 예측할 수 있게 되었다(Zhang, 2008b). 이러한 예측 단백질 모델은 컴퓨터 상에서 가상 화합물 스크리닝(virtual compound screening) 및 리간드 결합 연구에 적용될 수 있고, 이러한 새로운 지표를 이용하여 FDA에 승인된 약을 신약으로 재창출하는 것은 임상 시험 시간과 비용에 있어서 효율적이다(Chong and Sullivan, 2007). Recently, computer algorithms for predicting protein structure have been developed, enabling the prediction of the three-dimensional (3D) structure of the target protein from amino acid sequences (Zhang, 2008b). These predictive protein models can be applied to virtual compound screening and ligand binding studies on a computer, and using these new indicators to regenerate FDA-approved drugs into new drugs is an efficient, (Chong and Sullivan, 2007).
본 발명자는 소포체(ER)에 존재하는 Ca2+ 결합 단백질인 칼루미닌(calumenin)을 새로운 약물의 표적 단백질로 선정하였다.The present inventors have selected calumenin, a Ca 2+ binding protein present in the ER as a target protein for a new drug.
따라서, 본 발명에서는 선충(C. elegans, B. malayi 및 O. volvulus)의 calumenin 및 인간(H. sapiens) calumenin의 구조 모델링 결과를 분석하여, 대상 약물의 가상 스크리닝을 통해 사상충증 치료용 약물을 개발하고자 하였다. Therefore, in the present invention, the structural modeling results of calumenin and human (H. sapiens) calumenin of nematodes (C. elegans, B. malayi and O. volvulus) were analyzed and a drug for treatment of river blindness was developed through virtual screening of the target drug .
기존의 사상충증 치료제는 (ⅰ) 미세사상충을 배출하는 성충 사상충을 사멸시키지 못하는 문제, (ⅱ) 약물에 대한 내성이 생기는 문제, (ⅲ) 사상충에 대한 특이성 및 선택성이 낮은 문제를 갖고 있었다. Conventional treatments for onchocerciasis have problems in that (i) they do not kill adult pathogens that excrete microcephaly, (ii) they cause resistance to drugs, and (iii) they have low specificity and selectivity for pathogens.
본 발명자들은 이를 해결하기 위해, 사상충에 대한 특이적 표적으로 calumenin을 선정하여 사상충의 calumenin에 특이적으로 결합하는 새로운 사상충증 치료제를 개발하였다.In order to solve this problem, the present inventors have selected calumenin as a specific target for insect pests and have developed a novel treatment for river insect pestis that specifically binds to calumenin of the pathogens.
본 발명자는 이트라코나졸(Itraconazole), 이다루비신(Idarubicin), 팔리페리돈(Paliperidone) 및 다우노루비신(Daunorubicin)의 사상충증 치료용 신규한 용도를 확인하여, 본 발명에 이르게 되었다.The present inventor has identified a novel use for the treatment of onchocerciasis of Itraconazole, Idarubicin, Paliperidone and Daunorubicin, leading to the present invention.
본 발명은 이트라코나졸(Itraconazole), 이다루비신(Idarubicin), 팔리페리돈(Paliperidone) 및 다우노루비신(Daunorubicin)으로 이루어진 군에서 선택되는 하나 이상의 화합물 또는 이들의 염을 포함하는 사상충증(filariasis) 치료용 약학적 조성물을 제공한다.The present invention relates to a pharmaceutical composition for the treatment of filariasis comprising at least one compound selected from the group consisting of Itraconazole, Idarubicin, Paliperidone and Daunorubicin, Gt;
본 발명은 또한 사상충의 칼루미닌(calumenin)에 특이적으로 결합하는 사상충증 치료용 의약품의 스크리닝 방법을 제공한다. The present invention also provides a screening method for treating onchocerciasis, which specifically binds to calumenin of the pathogen.
본 발명은 여기에 제한되지 않으며, 언급되지 않은 또 다른 목적들은 아래의 기재로부터 통상의 기술자에게 명확하게 이해될 수 있다.The present invention is not limited thereto, and other objects not mentioned may be clearly understood by those skilled in the art from the following description.
본 발명은 이트라코나졸(Itraconazole), 이다루비신(Idarubicin), 팔리페리돈(Paliperidone) 및 다우노루비신(Daunorubicin)으로 이루어진 군에서 선택되는 하나 이상의 화합물 또는 이들의 염을 포함하는 사상충증(filariasis) 치료용 약학적 조성물을 제공한다.The present invention relates to a pharmaceutical composition for the treatment of filariasis comprising at least one compound selected from the group consisting of Itraconazole, Idarubicin, Paliperidone and Daunorubicin, Gt;
또한, 본 발명의 상기 화합물 또는 이들의 염은 사상충증을 일으키는 사상충의 calumenin과 특이적으로 결합할 수 있다. In addition, the compound of the present invention or a salt thereof can specifically bind to calumenin of onion flukes causing onchocerciasis.
또한, 상기 화합물 또는 이들의 염은 사상충증을 일으키는 사상충의 큐티클(cuticle) 생성을 억제할 수 있다.In addition, the compound or a salt thereof can inhibit the production of cuticle of onion flies causing onchocerciasis.
본 발명자들은 인간 calumenin에 상대적으로 낮은 결합 친화력을 가지며, 선충의 calumenin에 대한 특이성을 갖는 약물 후보 물질을 선별하기 위해, 선충 calumenin에만 높은 친화성을 나타내는 화학 물질을 분류했다. 그 결과, Itraconazole, Idarubicin, Paliperidone 및 Daunorubicin hydrochloride을 유효 물질의 후보로 선정하였으나, 이에 제한되지 않는다. The present inventors have classified chemicals exhibiting high affinity only to the nematode calumenin in order to select drug candidates having a relatively low binding affinity to human calumenin and having specificity for calumenin of the nematode. As a result, Itraconazole, Idarubicin, Paliperidone, and Daunorubicin hydrochloride were selected as candidates for the active substance, but not limited thereto.
Itraconazole은 스테롤 생합성(sterol biosynthesis)에 관여한다. Itraconazole은 lanosterol을 곰팡이 세포막의 필수 성분인 ergosterol으로 전환시키는 lanosterol 14-α-demethylase 효소를 억제하여, 항진균 효과가 있는 것으로 알려져 있다(Carrillo-Munoz et al., 2006; Gachotte et al., 1997; Henry et. al., 2000).Itraconazole is involved in sterol biosynthesis. Itraconazole is known to have an antifungal effect by inhibiting lanosterol 14-α-demethylase enzyme, which converts lanosterol to ergosterol, an essential component of the cell membrane (Carrillo-Munoz et al., 2006; Gachotte et al., 1997; Henry et al., 2000).
Idarubicin은 daunorubicin hydrochloride의 4-demethoxy 유사체로서, 이들과 동일한 약리학적 성질을 나타내며(Bigioni et al., 1994; Fukushima et al., 1993; Hollingshead and Faulds, 1991), 백혈병 치료제로 알려져 있다. Idarubicin is a 4-demethoxy analogue of daunorubicin hydrochloride and has the same pharmacological properties as these (Bigioni et al., 1994; Fukushima et al., 1993; Hollingshead and Faulds, 1991).
Paliperidone은 도파민 D2 수용체 길항제 및 세로토닌 5-HT2 수용체에 대한 길항제로서 작용함으로써 정신분열증을 치료 효과를 나타낸다(Cohen, 1994; He and Richardson, 1995; Leysen et. al., 1994).Paliperidone has a therapeutic effect on schizophrenia by acting as a dopamine D2 receptor antagonist and antagonist to the serotonin 5-HT2 receptor (Cohen, 1994; He and Richardson, 1995; Leysen et al., 1994).
Daunorubicin은 이중 가닥 DNA를 삽입함으로써 DNA와 RNA 합성을 억제하는 강력한 항암제로 알려져 있다(Aubel-Sadron and Londos-Gagliardi, 1984). 또한 DNA topoisomerase II의 억제제 역할을 하여 DNA 복제, 복구 및 RNA 및 단백질 합성을 억제한다 (Zunino and Capranico, 1990). Daunorubicin is known to be a potent anticancer drug that inhibits DNA and RNA synthesis by inserting double-stranded DNA (Aubel-Sadron and Londos-Gagliardi, 1984). It also acts as an inhibitor of DNA topoisomerase II, inhibiting DNA replication, repair, and RNA and protein synthesis (Zunino and Capranico, 1990).
바람직하게, 본 발명은 이트라코나졸(Itraconazole) 또는 이들의 염을 포함하는 사상충증(filariasis) 치료용 약학적 조성물을 제공한다.Preferably, the present invention provides a pharmaceutical composition for the treatment of filariasis comprising itraconazole or salts thereof.
효모, 식물, 곤충 및 포유 동물에는 복잡한 스테롤 생합성 경로가 있으나, 자유 생활(free living) 선충 및 기생 생활 선충은 스테롤을 합성 할 수 없으므로 생존을 위해 외인성 스테롤을 보충해야 한다(Chitwood, 1999; Hieb and Rothstein, 1968). 이는 스테롤이 자유 생활 선충과 기생 선충의 탈피호르몬(ecdysteroid)의 전구체이기 때문에, 본 발명자는 스테롤 생합성의 억제제인 Itraconazole이 사상충증 치료제로서의 가능성이 높다고 판단하였으며, 본 발명의 스크리닝 방법을 통하여 이를 확인하였다.There are complex sterol biosynthetic pathways in yeast, plants, insects and mammals, but free living and parasitic nematodes can not synthesize sterols and thus need to supplement the exogenous sterols for survival (Chitwood, 1999; Hieb and Rothstein, 1968). Since the sterol is a precursor of free living nematode and parasitic nematode ecdysteroid, the present inventor has determined that itraconazole, which is an inhibitor of sterol biosynthesis, has a high possibility as a treatment for onchocerciasis, and confirmed this through the screening method of the present invention.
또한, 본 발명의 약학적 조성물은 다이에틸카바마진(Diethylcarbamazine, DEC), 멕티잔(Mectizan), 알벤다졸(Albendazole) 및 이버멕틴(Ivermectine)으로 이루어진 군에서 선택되는 하나 이상의 화합물을 추가로 포함할 수 있다. The pharmaceutical composition of the present invention may further comprise at least one compound selected from the group consisting of Diethylcarbamazine (DEC), Mectizan, Albendazole and Ivermectine can do.
본 발명의 상기 사상충증은 림프사상충증(lymphatic filariasis) 또는 회선사상충증(onchocerciasis)일 수 있다. 또한, 본 발명의 상기 사상충증의 원인이 되는 사상충이 말레이사상충(Brugia malayi) 또는 회선사상충(Onchocerca volvulus)일 수 있으나, 이에 제한되지 않는다.The onchocerciasis of the present invention may be lymphatic filariasis or onchocerciasis. In addition, the causal organism causing the onchocerciasis of the present invention may be, but is not limited to, Brugia malayi or Onchocerca volvulus.
본 발명은 사상충의 칼루미닌(calumenin)에 특이적으로 결합하는 사상충증 치료용 의약품의 스크리닝(screening) 방법을 제공한다. The present invention provides a screening method of a drug for treating onchocerciasis which specifically binds to calumenin of the pathogen.
상기 사상충증 치료용 의약품의 스크리닝(screening) 방법은 하기의 단계를 포함할 수 있다:The screening method for treating onchocerciasis may include the following steps:
(a) 사상충의 칼루미닌(calumenin) 및 인간의 칼루미닌(calumenin)의 3D 구조를 예측하는 단계;(a) predicting the 3D structure of californicin and calumenin of the wasp strand;
(b) 사상충의 칼루미닌(calumenin)과 인간의 칼루미닌(calumenin) 간의 3D 구조 상동성을 측정하는 단계;(b) measuring the 3D structural homology between calmainin of californium and calumenin of human;
(c) 후보 물질 리간드 라이브러리(ligand library)에서 선택되는 하나 이상의 리간드를 사상충의 칼루미닌(calumenin) 및 인간의 칼루미닌(calumenin)과 도킹시키는 단계; 및(c) docking one or more ligands selected from a candidate material ligand library with calmenin and calumenin of the wasp strand; And
(d) 상기 도킹된 리간드와 칼루미닌(calumenin) 간의 결합 친화도를 분석하여 사상충의 칼루미닌(calumenin)에 특이적으로 결합하는 리간드를 선택하는 단계. (d) analyzing the binding affinity between the docked ligand and calumenin to select a ligand that specifically binds to calumenin of the pathogen.
상기 (a) 단계의 3D 구조는 I-TASSER 프로그램을 통하여 예측될 수 있으나, 이에 제한되지 않는다.The 3D structure of the step (a) can be predicted through the I-TASSER program, but is not limited thereto.
상기 (b) 단계의 상동성은 PyMOL 프로그램을 통하여 RMSD 값으로 측정할 수 있으나, 이에 제한되지 않는다.The homology of step (b) may be measured by RMSD value through the PyMOL program, but is not limited thereto.
상기 (c)단계의 도킹은 AutoDock Vina를 포함한 PyRx 컴퓨터 프로그램을 이용할 수 있으며, 이에 제한되지 않는다.The docking in step (c) may use a PyRx computer program including AutoDock Vina, but is not limited thereto.
상기 (d)단계의 결합 친화도는 컴퓨터 프로그램을 통해 리간드와 칼루미닌(calumenin) 간의 결합 에너지를 통해 계산할 수 있으며, 이에 제한되지 않는다.The binding affinity of step (d) may be calculated through binding energy between the ligand and calumenin through a computer program, but is not limited thereto.
본 발명의 사상충증(filariasis) 치료 또는 예방용 약학적 조성물은 기존의 사상충증 치료제와 달리 사상충에 대해서 특이적이고 선택적인 치료가 가능하고, 인체에 대한 부작용을 감소시킬 수 있으며, 성충 사상충을 효과적으로 사멸시킬 수 있다.The pharmaceutical composition for the treatment or prevention of filariasis of the present invention is capable of treating a selective and selective treatment for a pathogen, unlike the conventional treatment for river blindness, capable of reducing adverse effects on the human body, have.
또한, 본 발명의 사상충증 치료용 의약품의 스크리닝 방법은 사전에 사상충 치료에 대한 효과를 예측할 수 있어, 의약품 개발에 대한 엄청난 비용과 시간을 절약할 수 있다.In addition, the screening method of the medicament for treating onchocerciasis of the present invention can predict the effect on the treatment of onionism in advance, which can save enormous cost and time for drug development.
도 1은 C. elegans의 calumenin(Ce_calu), B. malayi의 calumenin(Bm_calu), O. volvulus의 calumenin(Ov_calu) 및 H. sapiens의 calumenin(Hs_calu)의 아미노산 서열을 나타낸다.
도 2는 C. elegans의 calumenin(Ce_calu), B. malayi의 calumenin(Bm_calu), O. volvulus의 calumenin(Ov_calu) 및 H. sapiens의 calumenin(Hs_calu)의 3D 구조를 나타낸다.
도 3은 사상충 및 인간의 calumenin 간의 구조 정렬을 통하여 RMSD 값을 계산한 결과를 나타낸다.
도 4는 Itraconazole의 화학식, 3D 구조 및 Itraconazole이 CeCALU-1에 도킹하는 형태를 나타낸다.
도 5는 Albendazole 또는 Ivermectin에 대한 calu-1(tm1783) 돌연변이의 민감도를 측정한 실험 결과를 나타낸다.
도 6은 Itraconazole에 대한 calu-1(tm1783)의 저항성을 측정한 실험 결과를 나타낸다. Figure 1 shows the amino acid sequences of calumenin (Ce_calu) of C. elegans, calumenin (Bm_calu) of B. malayi, calumenin (Ov_calu) of O. volvulus and calumenin (Hs_calu) of H. sapiens.
Fig. 2 shows the 3D structure of calumenin (Ce_calu) of C. elegans, calumenin (Bm_calu) of B. malayi, calumenin (Ov_calu) of O. volvulus and calumenin (Hs_calu) of H. sapiens.
Figure 3 shows the results of calculating the RMSD values through structural alignment between the canine and human calumenin.
Figure 4 shows the Itraconazole formula, 3D structure, and Itraconazole docking to CeCALU-1.
Figure 5 shows the results of the assay for the sensitivity of calu-1 (tm1783) mutations to Albendazole or Ivermectin.
Figure 6 shows the results of an experiment measuring the resistance of calu-1 (tm1783) to Itraconazole.
달리 정의되지 않는 한, 본 명세서에서 사용되는 모든 기술 용어 및 과학 용어는 본 분야의 통상의 기술자에 의해 일반적으로 이해되는 것과 동일한 의미를 가진다. 본 명세서에 기술된 것과 유사하거나, 또는 등가인 임의의 방법 및 물질은 본 명세서에 개시된 실시태양을 실시하는 데 사용될 수 있다.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Any methods and materials similar or equivalent to those described herein can be used to practice the embodiments disclosed herein.
"칼루미닌(calumenin)"은 소포체에 존재하고, Ca2+와 결합하는 효소로서, CALU 유전자에 의해서 코딩된다. "Calumenin" is an enzyme that exists in the endoplasmic reticulum and binds to Ca 2+, and is encoded by the CALU gene.
본 명세서에 사용된 용어 "리간드"란 생체 분자에 결합할 수 있는 분자이다. 일부 리간드는 활성 부위와 결합하지만, 촉매성 변환은 일어나지 않는다. 예로는 약물 디자인 분야에서 평가되는 리간드를 포함한다. 상기 리간드는 약리학적 목적으로 표적 생체분자와 비공유적으로 결합할 수 있는 그의 능력에 대해 선택되는 소형 분자일 수 있다. 일부 경우에서, 리간드는 생체 분자의 천연 거동을 강화시키거나, 활성화시키거나, 또는 억제시킬 수 있는 능력에 대해 평가된다.The term "ligand" as used herein is a molecule capable of binding to a biomolecule. Some ligands bind to the active site, but no catalytic conversion occurs. Examples include ligands that are evaluated in the field of drug design. The ligand may be a small molecule selected for its ability to non-covalently bind to a target biomolecule for pharmacological purposes. In some cases, the ligand is evaluated for its ability to enhance, activate, or inhibit the natural behavior of the biomolecule.
본 명세서에 사용된 용어 "라이브러리"는 2개 이상의 상이한 분자, 문자열, 및/또는 모델, 예컨대, 핵산 서열(예컨대, 유전자, 올리고뉴클레오티드 등) 또는 그로부터의 발현 생성물(예컨대, 효소 또는 다른 단백질)로 이루어진 집합을 의미한다. 라이브러리는 일반적으로 다수의 상이한 분자를 포함한다. 예를 들어, 라이브러리는 전형적으로 약 10개 이상의 상이한 분자를 포함한다. 거대 라이브러리는 전형적으로 약 100개 이상의 상이한 분자, 더욱 전형적으로, 약 1,000개 이상의 상이한 분자를 포함한다. 일부 적용을 위해, 라이브러리는 적어도 약 10,000개 이상의 상이한 분자를 포함한다. The term "library" as used herein refers to a nucleic acid sequence (e.g., a gene, oligonucleotide, etc.) or an expression product (e.g., an enzyme or other protein) therefrom of two or more different molecules, . Libraries generally contain a large number of different molecules. For example, a library typically comprises about ten or more different molecules. The macromolecule typically contains about 100 or more different molecules, more typically, about 1,000 or more different molecules. For some applications, the library comprises at least about 10,000 different molecules.
본 명세서에 사용된 용어 "도킹(docking)"이란 분자(예컨대, 기질 또는 리간드)와 생체 분자(예컨대, 효소 또는 단백질)의 활성 부위의 결합을 시뮬레이션하거나, 특징화(characterize)하는 컴퓨터에 의한 프로세스를 의미한다. 도킹은 전형적으로 "도커" 컴퓨터 프로그램을 사용하여 컴퓨터 시스템에서 실행된다.The term "docking " as used herein refers to a process by a computer that simulates or characterizes the binding of the active site of a molecule (e.g., a substrate or ligand) to a biomolecule (e.g., . Docking is typically performed on a computer system using a "doorker" computer program.
본 명세서에 사용된 용어 "스크리닝"이란 하나 이상의 생체분자의 하나 이상의 특성을 측정하는 프로세스를 의미한다. 예를 들어, 전형적인 스크리닝 프로세스는 하나 이상의 라이브러리의 하나 이상의 구성원의 하나 이상의 특성을 측정하는 것을 포함한다. 스크리닝은 생체분자의 전산 모델 및 생체분자의 가상 환경을 사용하여 전산적으로 수행될 수 있다.The term "screening " as used herein refers to a process of measuring one or more characteristics of one or more biomolecules. For example, a typical screening process involves measuring one or more characteristics of one or more members of one or more libraries. Screening can be performed computationally using computational models of biomolecules and virtual environments of biomolecules.
본 명세서에 사용된 용어 "상동성"은 구조적 상동성(structural homology)을 의미하며, 구조적 상동성이란, 특징적인 아미노산 서열로 인해서 삼차원(3D) 형태로 접혀서(folding) 존재하는 두 개 이상의 단백질의 삼차원 구조 간의 상대적인 동일성을 의미한다. 구조적 상동성은 0% 내지 100% 범위 내에서 결정되고, 두 개 또는 그 이상의 삼차원 구조 사이의 거리 차이, RMSD 및 TM-score 등을 이용하여 상동성을 계산할 수 있는 상업적으로 유용한 컴퓨터 프로그램을 사용하여 결정될 수 있다. 본 발명에서는 "PyMOL" 컴퓨터 프로그램을 이용하여 계산하였다.As used herein, the term "homology" refers to structural homology, and structural homology refers to the structural homology of two or more proteins that are folded in a three-dimensional (3D) Dimensional structure. Structural homology is determined within the range of 0% to 100%, and is determined using commercially available computer programs that can calculate homology using distance differences between two or more three-dimensional structures, RMSD and TM-score, etc. . In the present invention, calculation was performed using a "PyMOL" computer program.
또한, "서열 상동성"은 대상 서열과 비교하여 하나 또는 수 개의 부가, 결실 및/또는 치환을 갖는 아미노산 서열 또는 뉴클레오티드 서열과의 상동성을 포함하는 것으로 해석된다.In addition, "sequence homology" is interpreted to include homology with an amino acid sequence or a nucleotide sequence having one or several additions, deletions and / or substitutions compared to the subject sequence.
본 명세서에 사용된 용어 "I-TASSER(Iterative Threading ASSEmbly Refinement)"는 아미노산 서열로부터 단백질 분자의 입체 구조 모델을 예측하는 생물 정보학적 프로그램을 의미한다.As used herein, the term " I-TASSER (Iterative Threading ASSEmbly Refinement) "refers to a bioinformatic program that predicts a stereostructure model of a protein molecule from an amino acid sequence.
본 명세서에 사용된 용어 "PyRx"는 약물 표적에 대한 화합물의 라이브러리를 스크리닝하는데 사용할 수 있는 Virtual Screening 소프트웨어를 의미한다.As used herein, the term "PyRx" refers to Virtual Screening software that can be used to screen libraries of compounds for drug targets.
본 명세서에 사용된 용어 "AutoDock Vina"은 단백질과 리간드 간의 도킹에 효과적인 분자 모델링 시뮬레이션 소프트웨어를 의미한다. The term " AutoDock Vina "as used herein refers to molecular modeling simulation software effective for docking proteins and ligands.
본 발명의 약학적 조성물은 약제학적으로 허용되는 담체를 포함한다. 본 발명의 약학적 조성물에 포함되는 담체는 통상적으로 사용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. Carriers included in the pharmaceutical composition of the present invention are those conventionally used and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 발명의 약학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제 및 보존제 등을 추가로 포함할 수 있다.The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components.
본 발명의 약학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on such factors as formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, route of administration, excretion rate, .
본 발명의 약학적 조성물은 경구 또는 비경구로 투여될 수 있고, 비경구로 투여되는 경우, 정맥내 주입, 피하주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여될 수 있다. The pharmaceutical composition of the present invention can be administered orally or parenterally, and when administered parenterally, it can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration, and the like.
[실시예][Example]
본 발명에서는 선충의 calumenin과 인간의 calumenin 간의 상동성을 평가하고, 가상 스크리닝을 통하여 여러가지 화합물의 사상충증 치료제로서의 용도를 확인하였다. 이에 대한 가능성을 확인하기 위하여 C. elegans의 calumenin 돌연변이 모델 및 C. elegans의 야생형 및 C. elegans의 콜라겐 생합성에 관여하는 prolyl 4- hydroxylase의 α subunit이 결실된 dpy-18(e364) 돌연변이 모델을 사용하여 시험하였다.In the present invention, the homology between the calumenin of the nematode and the human calumenin was evaluated, and the use of various compounds as a treatment for onchocerciasis was confirmed through virtual screening. To confirm the possibility of this, we used the dpy-18 (e364) mutant model in which C. elegans calumenin mutant model and C. elegans wild type and C. elegans collagen biosynthetic prolyl 4-hydroxylase α subunit were deleted Respectively.
[실시예 1] 타겟 단백질의 구조 모델링 및 상동성 평가 [Example 1] Structural modeling and homology evaluation of target protein
타겟 단백질의 아미노산 서열The amino acid sequence of the target protein
CeCALU-1(GenBank 기탁 번호 AAF34189.1), BmCALU-1(Bm5089), OvCALU-1(OVOC5386) 및 HsCALU-1(GenBank 기탁 번호 AAB97725.1)의 아미노산 서열을 사용하여 각 종(species)의 calumenin 구조를 예측했다. The amino acid sequences of CeCALU-1 (GenBank Accession No. AAF34189.1), BmCALU-1 (Bm5089), OvCALU-1 (OVOC5386), and HsCALU-1 (GenBank Accession No. AAB97725.1) Predicted structure.
도 1에서 C. elegans의 calumenin(Ce_calu), B. malayi의 calumenin(Bm_calu), O. volvulus의 calumenin(Ov_calu) 및 H. sapiens의 calumenin(Hs_calu)의 아미노산 서열 정렬을 나타내었고, 그 중에서 칼슘과 결합하는 5개의 EF hands motif를 자홍색, 주황색, 노랑색, 빨강색, 청록색의 순서대로 나타내었으며, 인간 calumenin의 추가적인 EF hands motif는 파랑색과 녹색으로 나타내었다. Clustal X를 이용하여 다중 서열 정렬 하였으며, GeneDoc을 이용해 정렬 데이터를 시각화하였다. Figure 1 shows the amino acid sequence alignment of C. elegans calumenin (Ce_calu), B. malayi calumenin (Bm_calu), O. volvulus calumenin (Ov_calu) and H. sapiens calumenin (Hs_calu) Five EF hands motifs were combined in magenta, orange, yellow, red, and cyan order. Additional EF hands motifs of human calumenin were shown in blue and green. Clustal X was used for multiple sequence alignment, and the alignment data was visualized using GeneDoc.
도 1의 아미노산 서열 정렬을 통해서, 인간 및 선충의 calumenin 간에 구조적 차이를 확인하였다. Through the amino acid sequence alignment of Figure 1, structural differences between human and nematode calumenin were identified.
C. elegans의 caluemnin(CeCALU-1)은 나머지 사상충 선충의 calumenin과 72%의 서열 상동성이 있다. 반면에, 인간의 calumenin(HsCALU-1)은 C. elegans의 calumenin과 45%의 서열 상동성을, B. malayi의 calumenin(BmCALU-1)과 43%의 서열 상동성을, O. volvulus의 calumenin(OvCALU-1)과 44%의 서열 상동성을 가지는 것을 확인하였다.Caluemnin (CeCALU-1) from C. elegans is 72% homologous to calumenin of the other weevil nematodes. On the other hand, human calumenin (HsCALU-1) showed 45% sequence homology with calumenin of C. elegans and 43% sequence homology with calumenin (BmCALU-1) of B. malayi with calumenin of O. volvulus (OvCALU-1) and 44% sequence homology.
사상충의 calumenin은 5개로 추정되는 EF hands motif(칼슘이 결합하는 단백질)를 가지고 있으나, 인간 calumenin은 EF hands motif를 7개 가지고 있는 점 및 선충에만 C-terminal ER 보존 신호로 PAEL이 있다는 점에서 차이를 나타내었다. Calumenin has five EF hands motifs (calcium binding proteins), but human calumenin has seven EF hands motifs and PAEL is a C-terminal ER conserved signal only in nematodes. Respectively.
타겟 단백질의 3D 구조 및 상동성 평가3D structure and homology evaluation of target protein
단백질 구조 예측 모델은 I-TASSER(Roy et al., 2010; Yang et al., 2015; Yang and Zhang, 2015; Zhang, 2008a)를 이용하여 분석하였고, PyMOL(The PyMOL Molecular Graphics System, Version 1.8 Schrφdinger, LLC)을 이용해 시각화했다(도 2). The protein structure prediction model was analyzed using I-TASSER (Roy et al., 2010; Yang et al., 2015; Yang and Zhang, 2015; Zhang, 2008a) and PyMOL (The PyMOL Molecular Graphics System, Version 1.8 Schrødinger , LLC) (Fig. 2).
도 2A는 C. elegans의 calumenin(CeCALU-1), 도 2B는 B. malayi의 calumenin(BmCALU-1), 도 2C는 O. volvulus의 calumenin(OvCALU-1), 도 2D는 H. sapiens의 calumenin(HsCALU-1)을 나타낸 것이다. 도 2의 모든 구조는 PyMOL을 사용하여 나타내었고, Ca2+가 결합하는 EF hands motif를 도 1와 같은 방법의 유채색으로 표시하였다.FIG. 2C shows calumenin (OvCALU-1) of O. volvulus, FIG. 2D shows calumenin (OvCALU-1) of H. sapiens, (HsCALU-1). All of the structures in FIG. 2 are shown using PyMOL, and the EF hands motif to which Ca 2+ binds is represented by the chromatic color of the method shown in FIG.
도 2에 따르면, 3개의 선충 calumenin의 전반적인 구조는 비슷하지만 인간 calumenin의 예측 구조와는 다르다는 것을 알 수 있다. 이러한 구조적 차이는 선충의 calumenin이 선택적이고, 특이적인 사상충증(Filariasis) 약물의 타겟 단백질이 될 수 있다는 것을 의미한다.2, it can be seen that the overall structure of the three nematode calumenins is similar, but different from the predicted structure of human calumenin. This structural difference implies that the nematode calumenin is the target protein of the selective and specific Filariasis drug.
각 단백질 모델의 신뢰도는 C-score에 의해 정량적으로 측정되었으며, C-score는 템플릿 정렬의 유의성과 구조 조립 시뮬레이션의 수렴 매개 변수를 기반으로 계산되었다. C-score는 a confidence score로서, 모델링에 사용한 주형(template)과의 서열 유의성과 구조 조립 시뮬레이션에서의 수렴 매개 변수를 기반으로 계산한다. I-TASSER 통계에 따르면, 일반적으로 C-score는 -5 내지 2의 값을 가지며, C-score > -1.5인 경우 정확한 위상(global topology)을 나타낸다.The reliability of each protein model was quantitatively determined by the C-score, and the C-score was calculated based on the template alignment significance and the convergence parameter of the structural assembly simulation. The C-score is a confidence score, calculated based on the significance of the sequence with the template used for modeling and the convergence parameter in the structural assembly simulation. According to I-TASSER statistics, the C-score generally has a value between -5 and 2, and a C-score> -1.5 indicates a global topology.
또한 모델링 예측 품질(the quality of the modeling prediction)을 측정하기 위해 TM-score 및 RMSD(root-mean-square deviation)를 계산했다. RMSD와 TM-score(Zhang and Skolnick, 2004)는 예측 모델과 기본 구조 사이의 거리를 측정하여 두 구조 간의 구조적 유사성을 평가하는 척도이다.The TM-score and root-mean-square deviation (RMSD) were also calculated to measure the quality of the modeling predictions. RMSD and TM-score (Zhang and Skolnick, 2004) measure the structural similarity between two structures by measuring the distance between the predicted model and the underlying structure.
TM-score는 template modeling score로서 두 단백질간의 3차원 구조의 차이를 측정한 파라미터이다.The TM-score is a template modeling score, a parameter that measures the difference in three-dimensional structure between two proteins.
TM-score에서는 큰 거리의 오차를 작은 거리의 오차보다 낮은 비중으로 계산하여, 값을 더 정확하게 만든다(Zhang and Skolnick, 2 004). 정의에 따르면, TM-score =0.17은 임의의 유사성을 의미하고 TM-score > 0.5는 정확한 위상(global topology) 모델을 나타낸다(표 1). In the TM-score, the error of large distances is calculated as a lower specific gravity than the error of small distances, making the value more accurate (Zhang and Skolnick, 2, 004). By definition, TM-score = 0.17 means any similarity and TM-score> 0.5 indicates a global topology model (Table 1).
RMSD 분석은 SuperPose를 이용하여 주형에 대한 평균 편차로 계산한다. SuperPose 웹 서버는 변형된 쿼터니언 고유치 접근방법(quaterion eigenvalue approaches)을 이용한 짝짓기(pairwise) 및 다중 단백질 구조 겹치기(superposition)를 계산한다. 상동성이 높은 주형인 경우, 전통적인 비교 모델링(CM)의 RMSD 값이 1 내지 2Å인 모델이 생성된다(Marti-Renom et al., 2000). threading과 상동성이 낮은 주형에 대해 비교 모델링(CM)을 한 경우에는 루프 영역(loop region)에서 에러(error)가 있을 수 있고, RMSD 값이 2 내지 5Å의 범위에 있다(Roy et al., 2010, Zhang, 2009).The RMSD analysis is calculated as the average deviation for the template using SuperPose. The SuperPose web server computes pairwise and multiple protein structure superposition using modified quaternion eigenvalue approaches. In the case of highly homogeneous templates, a model with a RMSD value of 1 to 2 Å is generated for traditional comparative modeling (Marti-Renom et al., 2000). In case of comparative modeling (CM) for a template with low homology to threading, there may be an error in the loop region and the RMSD value is in the range of 2 to 5 Å (Roy et al. 2010, Zhang, 2009).
각 모델에 대한 C-score, TM-score 및 RMSD를 하기 표 1에 나타내었다.The C-score, TM-score and RMSD for each model are shown in Table 1 below.
본 발명의 각 calumenin 간의 RMSD를 계산하기 위해 각 calumenin모델을 구조 정렬(structural alignment)하였다(도 3). 도 3A는 C. elegans calumenin(CeCALU-1)과 B. malayi calumenin(BmCALU-1)의 구조 정렬을, 도 3B)는 C. elegans calumenin(CeCALU-1)과 O. volvulus calumenin(OvCALU-1)의 구조 정렬을, 도 3C는 B. malayi calumenin (BmCALU-1)과 O. volvulus calumenin(OvCALU-1)의 구조 정렬을, 도 3D는 C. elegans calumenin(CeCALU-1)과 H. sapiens calumenin(HsCALU-1)의 구조 정렬을 나타낸 것이다. In order to calculate the RMSD between each calumenin of the present invention, each calumenin model was subjected to structural alignment (Fig. 3). FIG. 3A shows the structural alignment of C. elegans calumenin (CeCALU-1) and B. malayi calumenin (BmCALU-1), FIG. 3B shows C. elegans calumenin (CeCALU-1) and O. volvulus calumenin (OvCALU- 3C shows the structural alignment of B. malayi calumenin (BmCALU-1) and O. volvulus calumenin (OvCALU-1), FIG. 3D shows C. elegans calumenin (CeCALU-1) and H. sapiens calumenin HsCALU-1).
CeCALU-1은 녹색으로, BmCALU-1은 회색(도 3A) 또는 자주색(도 3C)으로, OvCALU-1 및 HsCALU-1은 회색으로 표시했으며, EF hands motif는 상기 도 1의 방법과 동일하게 표시하였다. 1 was green, BmCALU-1 was gray (FIG. 3A) or purple (FIG. 3C), OvCALU-1 and HsCALU-1 were gray and EF hands motif was displayed in the same manner as in FIG. Respectively.
도 3에 의해 선충의 calumenin 간에는 겹치는 구조가 많으나, 인간과 선충의 calumenin 간에는 겹치는 구조가 적다는 것을 알 수 있다. FIG. 3 shows that there are many overlapping structures between the calumenin of the nematode, but the overlapping structure between the human and the calumenin of the nematode is small.
CeCALU-1 모델은 BmCALU-1(RMSD = 1.038Å, 도 4A) 및 OvCALU-1 모델(RMSD = 1.263Å, 도 4B)과 높은 구조적 유사성을 보였나, HsCALU-1 모델과는 RMSD 값 차이가 컸다(20.627Å). 이는 선충과 인간 calumenin 구조 간에 유의미한 차이가 있음을 의미한다. BmCALU-1 모델과 OvCALU-1 모델은 RMSD 값 차이가 1.260Å(도 3C)을 가져 상호간 높은 구조적 유사성을 보였으나, HsCALU-1(RMSD = 19.877Å 및 19.918Å)과는 다른 구조적 특징을 보였다(도 4). The CeCALU-1 model showed a high structural similarity with the BmCALU-1 (RMSD = 1.038Å, Fig. 4A) and OvCALU-1 model (RMSD = 1.263Å, Fig. 4B) but the RMSD value difference was larger than the HsCALU-1 model 20.627A). This implies that there is a significant difference between nematode and human calumenin structure. The BmCALU-1 model and the OvCALU-1 model showed structural similarities with each other due to the RMSD value difference of 1.260 Å (Fig. 3C), but showed different structural features from HsCALU-1 (RMSD = 19.877 Å and 19.918 Å) 4).
이러한 결과는 선충의 종이 달라도 선충 간에는 calumenin 구조가 잘 보존되지만, 인간의 calumenin 구조와는 명백히 구별된다는 것을 의미한다. 이것은 선충의 calumenin이 사상충증(Filariasis) 치료용 약물의 선택적이고 특이적인 타겟이 될 수 있다는 것을 의미한다. These results indicate that the calumenin structure is well preserved among the nematode even if the nematode is different, but it is clearly distinguished from the human calumenin structure. This means that the nematode calumenin can be a selective and specific target for the treatment of filariasis.
[실시예 2] 분자 도킹에 의한 가상 약물 스크리닝[Example 2] Virtual drug screening by molecular docking
리간드 라이브러리 선정 Selection of ligand library
1,701개의 상업적으로 이용 가능한 약물이 포함된 분자 집단(Zdd library)은 ZINC database(the ZINC drug database Version 12, http://zinc.docking.org, Irwin and Shoichet, 2005)로부터 얻었다. 1,701 화합물의 Zdd 라이브러리는 오픈 소스 가상 스크리닝 소프트웨어인 PyRx를 사용하여 선별되었다(Dallakyan and Olson, 2015).A molecular population (Zdd library) containing 1,701 commercially available drugs was obtained from the ZINC database (ZINC drug database Version 12, http://zinc.docking.org, Irwin and Shoichet, 2005). The Zdd library of 1,701 compounds was screened using PyRx, an open-source virtual screening software (Dallakyan and Olson, 2015).
분자 도킹 분석Molecular docking analysis
PyRx/AutoDock Vina(Version 0.8) 프로그램을 이용하여 예상되는 calumenin의 3D 모델에 분자 도킹을 하는 화합물을 선별하였다. We used the PyRx / AutoDock Vina (Version 0.8) program to select compounds that will molecular dock into the expected 3D model of calumenin.
각 caluemnin 모델과 리간드(ligand) 간의 결합 에너지를 측정하여 스크리닝하였다. 구체적으로 인간 calumenin(HsCALU-1)에 결합하지 않으면서 선충의 calumenin(CeCALU-1, BmCALU-1 및 OvCALU-1)에 특이적으로 결합하는 화합물을 찾기 위해 CeCALU-1, BmCALU-1, OvCALU-1 및 HsCALU-1의 개별 3D 구조를 이용하여 리간드를 선별했다. The binding energy between each caluemnin model and the ligand was measured and screened. BcCALU-1, BcCALU-1, and OvCALU-1 to specifically bind to calumenin (CeCALU-1, BmCALU-1 and OvCALU-1) of nematode without binding to human calumenin (HsCALU- 1 and HsCALU-1 were used to select ligands.
선별된 리간드를 CeCALU-1 모델과 리간드 사이의 결합 에너지가 작은 순서대로, 즉 리간드와 CeCALU-1 모델 간의 친화도가 높은 순서대로 표 2에 나열하였고, BmCALU-1, OvCALU-1 또는 HsCALU-1 모델에 대한 결합 친화도 순위를 기재하였다.The selected ligands are listed in Table 2 in the order of decreasing binding energy between the CeCALU-1 model and the ligand, that is, in the order of higher affinity between the ligand and the CeCALU-1 model, and BmCALU-1, OvCALU-1 or HsCALU- The order of binding affinity for the model is described.
인간 calumenin에 상대적으로 낮은 결합 친화력을 가지며, 선충의 calumenin에 대한 특이성을 갖는 사상충증 치료 또는 예방용 약물을 선별하기 위해, 선충 calumenin(CeCALU-1, BmCALU-1 및 OvCALU-1)에만 높은 친화성을 나타내는 화학 물질을 분류했다. 그 결과, Itraconazole, Idarubicin, Paliperidone 및 Daunorubicin hydrochloride을 유효 물질의 후보로 선정하였다. High affinity only to the nematode calumenin (CeCALU-1, BmCALU-1, and OvCALU-1) was used to screen drugs for treatment or prevention of onchocerciasis with relatively low binding affinity to human calumenin and specificity to calumenin of the nematode The chemicals that they represent are classified. As a result, Itraconazole, Idarubicin, Paliperidone and Daunorubicin hydrochloride were selected as candidates of active substances.
상기 [표 2]에서 보는 바와 같이, Itraconazole, Idarubicin, Paliperidone 및 Daunorubicin hydrochloride는 높은 선충 특이성을 갖는 것으로 확인되었으며, Itraconazole이 가장 높은 선충 특이성을 가지는 것으로 나타났다.As shown in Table 2, Itraconazole, Idarubicin, Paliperidone and Daunorubicin hydrochloride have high nematode specificity and itraconazole has the highest nematode specificity.
Itraconazole과 CeCALU-1의 calumenin 간의 도킹 상태는 PyMOL를 이용하여 시각화 하였다(도 4). Itraconazole의 화학적 구조 및 3D 구조를 도 4A에 나타내었다. 도 4B 내지 4E에서 Itraconazole과 CeCALU-1의 자세한 도킹 방식을 PyMOL를 이용하여 시각화하였다. Itraconazole은 CeCALU-1의 결합 포켓(binding pocket)과 도킹하며, 세 번째 EF hand motif(노란색으로 표시)에 연결된다. The docking state between Itraconazole and CeCALU-1 calumenin was visualized using PyMOL (Fig. 4). The chemical and 3D structures of Itraconazole are shown in Figure 4A. 4B to 4E, detailed docking schemes of Itraconazole and CeCALU-1 were visualized using PyMOL. Itraconazole is docked with the binding pocket of CeCALU-1 and connected to the third EF hand motif (marked yellow).
도 4를 통해 Itraconazole이 CeCALU-1의 calumenin과 안정적으로 결합한다는 것을 확인하였다. FIG. 4 shows that itraconazole is stably bound to calumenin of CeCALU-1.
[실시예 3] Itracozole과 calumenin 연관성 검증 [Example 3] Relationship between Itracozole and calumenin
실험의 준비Preparation of experiments
Itraconazole의 사상충증 치료 효과를 검증하기 위해, C. elegans 야생형인 N2(대조군), C. elegans의 콜라겐 생합성에 관여하는 prolyl 4- hydroxylase의 α subunit이 결실된 dpy-18(e364) 돌연변이(비교예), C. elegans의 calumenin이 결실된 calu-1(tm1783) 돌연변이(실시예)를 준비하였다. 대조군, 비교예 및 실시예는 L4 단계의 유충에서 24시간 키운 성충(1 day-old adult)으로 준비하였다. In order to examine the effect of Itraconazole on onchocerciasis, dpy-18 (e364) mutation (comparison example) in which C. elegans wild type N2 (control) and C. elegans collagen biosynthesis-related α subunit deletion of prolyl 4- , A calu-1 (tm1783) mutant (example) in which calumenin of C. elegans was deleted was prepared. The control, comparative, and example were prepared as adult (1 day-old adult) for 24 hours in L4 stage larvae.
상기 대조군 및 비교예는 the Caenorhabditis Genetics Center(CGC)에서 입수했고, 상기 실시예는 National BioResource Project(Japan)에서 입수했으며, 기생충 사육 방법은 표준 방법에 따랐다(Brenner, 1974). The control and comparative examples were obtained from the Caenorhabditis Genetics Center (CGC), which was obtained from the National BioResource Project (Japan) and the parasite method was followed by standard methods (Brenner, 1974).
상기 대조군, 비교예 및 실시예에 Albendazole(실험 1), Ivermectin(실험 2) 및 Itraconazole(실험 3)을 각각 처리하였다. 상기 Albendazole 및 상기 Ivermectin은 기존의 사상충증 치료제이고, Albendazole은 benzimidazole 계열의 약제이다. Ivermectin은 Streptomyces avermitilis에 의해 생산되는 항기생충성 항생물질인 Avermectin의 한 종류이다.Albendazole (Experiment 1), Ivermectin (Experiment 2) and Itraconazole (Experiment 3) were treated with the control, comparative and example, respectively. Albendazole and Ivermectin are conventional treatments for onchocerciasis, and albendazole is a benzimidazole-based drug. Ivermectin is a class of Avermectin, an anti-parasitic antibiotic produced by Streptomyces avermitilis.
상기 실험 1과 실험 2에서는 OP50 영양원이 포함된 고형 선충 성장 배지(nematode growth media, NGM)가 이용되었고, 실험 3에서는 80%(v/v)농도의 M9 buffer(22 mM KH2PO4, 42.3 mM Na2HPO4 and 85.6 mM NaCl) 및 20%(v/v) 농도의 OP50를 포함하는 액체 배양액이 사용되었다. 정확한 실험을 위하여 Itraconazole에 대한 실험용 선충 성장 배지에 콜레스테롤을 제외하였다. In
실험Experiment
실험 1 및 실험 2는 고형 성장 배지(solid plate)를 이용하였으며, 1 plate 당 10 내지 15마리의 대조군, 비교예 및 실시예를 올려놓고 20°C에서 배양하며 실험하였다. 실험 3은 96 well culture plate(Cat#32096, SPL, Republic of Korea)의 각 well에 상기 액체 배양액 100 ㎕ 및 기생충 1마리를 넣고, 20°C에서 배양하였다.
실험 1은 3일 동안 Albendazole에 노출시켜서 24시간 간격으로 대조군, 비교예 및 실시예의 생존율을 측정하였고, 실험 2는 2일 동안 Ivermectin에 노출시켜서 24시간 간격으로 대조군, 비교예 및 실시예의 생존율을 측정하였으며, 실험 3은 3일 동안 Itraconazole에 노출시켜서 24시간 간격으로 대조군, 비교예 및 실시예의 생존율을 측정하였다. 상기 측정은 최소 3번 반복하였다. In
기생충은 플레이트를 건드렸을 때 반응이 없는 경우와 기생충의 인두 움직임(pharyngeal pumping)이 없는 경우에도 죽은 것으로 간주하였다. 기생충이 플레이트 밖으로 기어 나온 경우에는 숫자를 세지 않았다.The parasite was considered dead when the plate was touched and there was no response and no pharyngeal pumping of the parasite. When the parasite came out of the plate, it did not count the number.
실험 1에서는 albendazole의 농도를 0, 6.25, 12.5 및 25 μM으로 조절했고, 실험 2에서는 Ivermectin의 농도를 0, 1.2, 2.4, 4.8 및 9.6 nM으로 조절했으며, 실험 3에서는 Itraconazole의 농도를 20, 40, 80 및 160 μM으로 조절하였다. In
결과 result
실험 1의 결과는 도 5A에 나타냈고, 실험 2의 결과는 도 5B에 나타냈으며, 실험 3의 결과는 도 6에 나타냈다. The results of
실험 1에서 실시예는 대조군에 비해 Albendazole의 농도에 따라 민감한 반응을 보였다(도 5A). 비교예는 대조군에 비해 Albendazole에 대한 민감성이 높았지만, 실시예 보다는 상대적으로 낮았다. In
실험 2에서 비교예와 실시예는 Ivermectin에 대한 비슷한 정도의 민감성이 나타났다. 대조군과의 차이는 Ivermectin을 투여한지 2일 후부터 나타났다. In Experiment 2, the comparative examples and the examples showed similar sensitivity to Ivermectin. Differences from the control group occurred 2 days after administration of Ivermectin.
이러한 결과는 큐티클(cuticle)의 결실이 기생충에 대한 효과적인 약물 전달을 유도할 수 있으며, 정상 표피 발달에 중요한 요소인 calumenin이 새로운 약물 표적이 될 수 있음을 의미한다.These results indicate that deletion of cuticle can induce effective drug delivery to parasites and calumenin, an important factor in normal epidermal development, can be a new drug target.
실험 3에서 실시예는 대조군 및 비교예 보다 Itraconazole에 대해 더 많은 내성을 가지는 표현형으로 나타났다(도 6). Calumenin 결손된 돌연변이 선충에 해당하는 실시예의 생존율은 160 μM Itraconazole에서 90% 이상이었지만, 대조군 및 비교예의 생존율은 같은 농도에서 약 74%와 38%를 나타내었다. 결과적으로, Itraconazole이 선충의 calumenin을 선택적이고 특이적으로 억제함으로써 사상충증의 치료 및 예방하는 효과를 갖는 것을 확인하였다.In Experiment 3, the example showed a more resistant phenotype to Itraconazole than the control and comparative examples (Fig. 6). Survival rates of the Calumenin-deficient mutant nematodes were greater than 90% in 160 μM Itraconazole, but survival rates of the control and comparative examples were about 74% and 38% at the same concentrations. As a result, Itraconazole selectively and specifically inhibited calumenin of the nematode, indicating that it has an effect of treating and preventing onchocerciasis.
Claims (5)
(b) 사상충의 칼루미닌(calumenin)과 인간의 칼루미닌(calumenin) 간의 3D 구조 상동성을 측정하는 단계;
(c) 후보 물질 리간드 라이브러리(ligand library)에서 선택되는 하나 이상의 리간드를 사상충의 칼루미닌(calumenin) 및 인간의 칼루미닌(calumenin)과 도킹시키는 단계; 및
(d) 상기 도킹에 대한 리간드와 칼루미닌(calumenin) 간의 결합 친화도를 분석하여 사상충의 칼루미닌(calumenin)에 특이적으로 결합하는 리간드를 선택하는 단계를 포함하는 것을 특징으로 하는 사상충증 치료용 또는 예방용 화합물의 스크리닝(screening) 방법.
(a) predicting the 3D structure of californicin and calumenin of the wasp strand;
(b) measuring the 3D structural homology between calmainin of californium and calumenin of human;
(c) docking one or more ligands selected from a candidate material ligand library with calmenin and calumenin of the wasp strand; And
(d) analyzing the binding affinity between the ligand and calumenin for the docking, and selecting a ligand that specifically binds to calumenin of the pathogen. A method of screening a preventive compound.
The screening method of claim 1, wherein the 3D structure of step (a) is predicted through an I-TASSER program.
The method according to claim 1, wherein the homology of step (b) is calculated as an RMSD value through a PyMOL program.
The screening method according to claim 1, wherein the docking in step (c) uses a PyRx computer program including AutoDock Vina.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020180142930A KR101945162B1 (en) | 2018-11-19 | 2018-11-19 | A method of screening a medicine for treating or preventing filariasis |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020180142930A KR101945162B1 (en) | 2018-11-19 | 2018-11-19 | A method of screening a medicine for treating or preventing filariasis |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020170111888A Division KR101970885B1 (en) | 2017-09-01 | 2017-09-01 | Pharmaceutical composition for treating or preventing filariasis and screening methods therefore |
Publications (1)
Publication Number | Publication Date |
---|---|
KR101945162B1 true KR101945162B1 (en) | 2019-02-01 |
Family
ID=65367726
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020180142930A KR101945162B1 (en) | 2018-11-19 | 2018-11-19 | A method of screening a medicine for treating or preventing filariasis |
Country Status (1)
Country | Link |
---|---|
KR (1) | KR101945162B1 (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008015014A2 (en) * | 2006-08-04 | 2008-02-07 | Humboldt-Universität Zu Berlin | Cystatin from nematodes in the treatment of autoimmune or allergic diseases |
KR20080012928A (en) * | 2005-05-06 | 2008-02-12 | 더 스크립스 리서치 인스티튜트 | Compositions and methods for modulating cells via cd14 and toll-like receptor 4 signaling pathway |
KR20150005239A (en) * | 2013-07-05 | 2015-01-14 | 인하대학교 산학협력단 | Pharmaceutical Compositions for Preventing or Treating a Microorganism Infection Disease Comprising a Chemical Compound with an Inhibitory Activity Against Phosphotransacetylase |
-
2018
- 2018-11-19 KR KR1020180142930A patent/KR101945162B1/en active IP Right Grant
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20080012928A (en) * | 2005-05-06 | 2008-02-12 | 더 스크립스 리서치 인스티튜트 | Compositions and methods for modulating cells via cd14 and toll-like receptor 4 signaling pathway |
WO2008015014A2 (en) * | 2006-08-04 | 2008-02-07 | Humboldt-Universität Zu Berlin | Cystatin from nematodes in the treatment of autoimmune or allergic diseases |
KR20150005239A (en) * | 2013-07-05 | 2015-01-14 | 인하대학교 산학협력단 | Pharmaceutical Compositions for Preventing or Treating a Microorganism Infection Disease Comprising a Chemical Compound with an Inhibitory Activity Against Phosphotransacetylase |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Cannon et al. | Efflux-mediated antifungal drug resistance | |
Thorens et al. | Glucose transporters in the 21st Century | |
Dermauw et al. | The ABC gene family in arthropods: comparative genomics and role in insecticide transport and resistance | |
Mastrocola et al. | Metaflammation: tissue-specific alterations of the NLRP3 inflammasome platform in metabolic syndrome | |
Bassaganya-Riera et al. | Abscisic acid regulates inflammation via ligand-binding domain-independent activation of peroxisome proliferator-activated receptor γ | |
Chen et al. | Recent progress in the discovery of myeloid differentiation 2 (MD2) modulators for inflammatory diseases | |
dos Santos Nascimento et al. | Drug repurposing: A strategy for discovering inhibitors against emerging viral infections | |
US20140088056A1 (en) | Cardiac glycosides are potent inhibitors of interferon-beta gene expression | |
CN107002086A (en) | Influenza A virus variant | |
CN107002052A (en) | Influenza A virus variant | |
DE602004011047T2 (en) | CRYSTAL STRUCTURE FROM THE HUMAN CORONAVIRUS 229E MAIN PROTEINASE AND ITS USE IN THE DEVELOPMENT OF SARS INHIBITORS | |
Mahmud et al. | Screening of potent phytochemical inhibitors against SARS-CoV-2 main protease: an integrative computational approach | |
Mullner et al. | Chemistry and pharmacology of neglected helminthic diseases | |
KR101945162B1 (en) | A method of screening a medicine for treating or preventing filariasis | |
Li et al. | Discovery of novel 7-hydroxy-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide derivatives with potent and selective antifungal activity against Cryptococcus species | |
US20070269420A1 (en) | Compounds, Compositions and Methods for Treatment and Prophylaxis of Hepatitis C Viral Infections and Associated Diseases | |
KR101970885B1 (en) | Pharmaceutical composition for treating or preventing filariasis and screening methods therefore | |
CN104812383A (en) | Combination of therapeutic agents for treating HCV infection | |
Su et al. | Protective effects of DcR3-SUMO on lipopolysaccharide-induced inflammatory cells and septic mice | |
Lu et al. | Effect of Swainsonine in Oxytropis kansuensis on golgi α-mannosidase II expression in the brain tissues of Sprague–Dawley rats | |
Zhang et al. | Salidroside promotes healthy longevity by interfering with HSP90 activity | |
KR20210061217A (en) | Composition for prevention or treatment of sepsis or septic shock comprising maslinic acid | |
Mayan et al. | Evaluation of selected natural compounds for cancer stem cells targeted anti-cancer activity: a molecular docking study | |
Menakha et al. | In silico prediction of drug molecule from Ipomoea sepiaria against Type 2 diabetes | |
CN108601772A (en) | Tacrolimus for treating TDP-43 protein sickness |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
E701 | Decision to grant or registration of patent right | ||
GRNT | Written decision to grant |