EP1644860A4 - Procede et programme informatique permettant de decouvrir des medicaments a l'aide d'un echantillonnage de metropolis monte carlo grand-canonique pondere - Google Patents
Procede et programme informatique permettant de decouvrir des medicaments a l'aide d'un echantillonnage de metropolis monte carlo grand-canonique pondereInfo
- Publication number
- EP1644860A4 EP1644860A4 EP04776948A EP04776948A EP1644860A4 EP 1644860 A4 EP1644860 A4 EP 1644860A4 EP 04776948 A EP04776948 A EP 04776948A EP 04776948 A EP04776948 A EP 04776948A EP 1644860 A4 EP1644860 A4 EP 1644860A4
- Authority
- EP
- European Patent Office
- Prior art keywords
- fragment
- computer
- fragments
- protein
- program code
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 44
- 238000004590 computer program Methods 0.000 title claims abstract description 20
- 238000012614 Monte-Carlo sampling Methods 0.000 title description 4
- 238000007876 drug discovery Methods 0.000 title description 3
- 239000012634 fragment Substances 0.000 claims abstract description 183
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 53
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 53
- 238000005070 sampling Methods 0.000 claims abstract description 35
- 239000003814 drug Substances 0.000 claims abstract description 23
- 229940079593 drug Drugs 0.000 claims abstract description 20
- 239000000126 substance Substances 0.000 claims abstract description 18
- 238000004088 simulation Methods 0.000 claims description 31
- 238000005381 potential energy Methods 0.000 claims description 15
- 238000000342 Monte Carlo simulation Methods 0.000 claims description 10
- 238000004458 analytical method Methods 0.000 claims description 8
- 230000000977 initiatory effect Effects 0.000 claims 2
- 241000269627 Amphiuma means Species 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 23
- 238000013459 approach Methods 0.000 abstract description 17
- 238000009826 distribution Methods 0.000 abstract description 13
- 238000002922 simulated annealing Methods 0.000 abstract description 7
- 230000003993 interaction Effects 0.000 description 29
- 238000004891 communication Methods 0.000 description 8
- 230000006854 communication Effects 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 7
- 238000004422 calculation algorithm Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 5
- 239000002245 particle Substances 0.000 description 4
- 238000004364 calculation method Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000000324 molecular mechanic Methods 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 238000005192 partition Methods 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000002424 x-ray crystallography Methods 0.000 description 3
- 238000003775 Density Functional Theory Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000009795 derivation Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 238000012804 iterative process Methods 0.000 description 2
- 230000009021 linear effect Effects 0.000 description 2
- 230000000869 mutational effect Effects 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 101710177166 Phosphoprotein Proteins 0.000 description 1
- 101710093543 Probable non-specific lipid-transfer protein Proteins 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000007621 cluster analysis Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004001 molecular interaction Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
Classifications
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
- G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
- G16C20/50—Molecular design, e.g. of drugs
-
- 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
- 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
- G16B15/30—Drug targeting using structural data; Docking or binding prediction
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
- G16C10/00—Computational theoretical chemistry, i.e. ICT specially adapted for theoretical aspects of quantum chemistry, molecular mechanics, molecular dynamics or the like
Definitions
- the invention described herein relates to models for molecular interaction, and in particular the use of such models for drug discovery.
- the MCSS approach for example is essentially based on an energy minimization procedure, providing fragment states corresponding to various local minima of the potential energy field representing the fragment- protein interaction.
- Such a procedure is computationally more expeditious than computing a thermodynamic ensemble of states, but is unable to provide information on entropic effects, essential for free energy estimates.
- the probability P(N) for having N fragments in the system is given by This is simply the Poisson distribution with parameter Z.
- the average number of fragments in the system is given by
- the association constant is the basic biologically relevant quantity.
- Equations (30), (31) and (32) provide the basic relations for interpreting the WGCMMC data.
- a first estimate of the binding affinity of a given fragment for different regions on the protein surface can be obtained by assigning a critical R c to each fragment-residue pair.
- These B c values are obtained from the WGCMMC data by applying relation (32), and by assigning a binding volume ⁇ V& to each residue based of the following proximity criteria:
- the Van der Walls radii are typically defined as half the Lennard-Jones parameter from the considered molecular-mechanics force-field (e.g. AMBER) used for the Monte Carlo simulation.
- Equations (42) to (47) can naturally be generalized to various types of biased sampling, such as preferential sampling or cavity bias.
- step 760 one may also compute the average potential energy of the clump: where E t is the potential energy of interaction of fragment i with the protein.
- secondary memory 810 may include other means for allowing computer programs or other instructions to be loaded into computer system 800.
- Such means may include, for example, a removable storage unit 822 and an interface 820.
- An example of such means may include a removable memory chip (such as an EPROM, or PROM) and associated socket, or other removable storage units 822 and interfaces 820 which allow software and data to be transferred from the removable storage unit 822 to computer system 800.
Landscapes
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physics & Mathematics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Computational Biology (AREA)
- Theoretical Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biotechnology (AREA)
- Evolutionary Biology (AREA)
- Biophysics (AREA)
- Medical Informatics (AREA)
- Medicinal Chemistry (AREA)
- Computing Systems (AREA)
- Management, Administration, Business Operations System, And Electronic Commerce (AREA)
- Peptides Or Proteins (AREA)
Abstract
Cette invention concerne un procédé et un programme informatique permettant de modéliser un système comprenant une protéine et une pluralité de types de fragments différents afin d'identifier des pistes thérapeutiques. Ce procédé repose sur une approche de Métropolis Monté Carlo pondérée consistant à échantillonner l'ensemble grand-canonique. Ce procédé diffère d'une approche de minimisation énergétique en ce qu'il produit des répartitions de fragments correspondant à des fluctuations thermiques à des températures physiologiquement pertinentes. Le mécanisme de Métropolis Monté Carlo pondéré effectue un échantillonnage quasi-uniforme de toutes les régions d'intérêt sur la protéine et permet ainsi de résoudre la vaste gamme de densités de la répartition thermodynamique, ce qui ne pourrait pas être obtenu par un mécanisme de Métropolis non pondéré. L'utilisation des propriétés de l'ensemble grand-canonique permet de calculer efficacement l'affinité de fragments pour différentes régions sur la surface de la protéine à l'aide d'un procédé appelé 'recuit simulé du potentiel chimique'. Un site de liaison à une protéine est ensuite identifié comme étant une région présentant une grande affinité pour de multiples fragments présentant un ensemble diversifié de propriétés physico-chimiques. A l'intérieur d'un site de liaison, l'assemblage de fragments en pistes thérapeutiques est finalement effectué sur la base de l'affinité de liaison des différents fragments, de la proximité géométrique et d'une variété de règles selon lesquelles des fragments organiques peuvent se lier les uns aux autres.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US48277403P | 2003-06-27 | 2003-06-27 | |
| US50927203P | 2003-10-08 | 2003-10-08 | |
| US50954303P | 2003-10-09 | 2003-10-09 | |
| US53168703P | 2003-12-23 | 2003-12-23 | |
| US10/748,708 US20040267509A1 (en) | 2003-06-27 | 2003-12-31 | Method and computer program product for drug discovery using weighted Grand Canonical Metropolis Monte Carlo sampling |
| US10/794,181 US20040267456A1 (en) | 2003-06-27 | 2004-03-08 | Method and computer program product for drug discovery using weighted grand canonical metropolis Monte Carlo sampling |
| PCT/US2004/020059 WO2005001645A2 (fr) | 2003-06-27 | 2004-06-25 | Procede et programme informatique permettant de decouvrir des medicaments a l'aide d'un echantillonnage de metropolis monte carlo grand-canonique pondere |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP1644860A2 EP1644860A2 (fr) | 2006-04-12 |
| EP1644860A4 true EP1644860A4 (fr) | 2008-08-06 |
Family
ID=33556805
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP04776948A Withdrawn EP1644860A4 (fr) | 2003-06-27 | 2004-06-25 | Procede et programme informatique permettant de decouvrir des medicaments a l'aide d'un echantillonnage de metropolis monte carlo grand-canonique pondere |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP1644860A4 (fr) |
| WO (1) | WO2005001645A2 (fr) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7415361B2 (en) * | 2003-12-09 | 2008-08-19 | Locus Pharmaceuticals, Inc. | Methods and systems for analyzing and determining ligand-residue interaction |
| EP1763814A4 (fr) * | 2004-06-07 | 2008-12-10 | Locus Pharmaceuticals Inc | Identification de ligands pour macromolecules |
| CN100442270C (zh) * | 2005-08-08 | 2008-12-10 | 上海市计量测试技术研究院 | 一种用蒙特卡罗统计模拟计算合成不确定度的方法 |
| WO2010090700A2 (fr) * | 2009-01-21 | 2010-08-12 | President And Fellows Of Harvard College | Systèmes et procédés de production et/ou de caractérisation de molécules à des fins pharmaceutiques et autres |
| CN109932713B (zh) * | 2019-03-04 | 2021-07-09 | 北京旷视科技有限公司 | 定位方法、装置、计算机设备、可读存储介质和机器人 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5884230A (en) * | 1993-04-28 | 1999-03-16 | Immunex Corporation | Method and system for protein modeling |
| US5453937A (en) * | 1993-04-28 | 1995-09-26 | Immunex Corporation | Method and system for protein modeling |
| US5600571A (en) * | 1994-01-18 | 1997-02-04 | The Trustees Of Columbia University In The City Of New York | Method for determining protein tertiary structure |
| US6251620B1 (en) * | 1995-08-30 | 2001-06-26 | Ariad Pharmaceuticals, Inc. | Three dimensional structure of a ZAP tyrosine protein kinase fragment and modeling methods |
| US6622094B2 (en) * | 1996-02-15 | 2003-09-16 | The Trustees Of Columbia University In The City Of New York | Method for determining relative energies of two or more different molecules |
| GB9616105D0 (en) * | 1996-07-31 | 1996-09-11 | Univ Kingston | TrkA binding site of NGF |
| US5854992A (en) * | 1996-09-26 | 1998-12-29 | President And Fellows Of Harvard College | System and method for structure-based drug design that includes accurate prediction of binding free energy |
| US6735530B1 (en) * | 1998-09-23 | 2004-05-11 | Sarnoff Corporation | Computational protein probing to identify binding sites |
| DE60026452T2 (de) * | 1999-04-06 | 2006-08-10 | Micromass Uk Ltd. | Verfahren zur Identifizierung von Peptidensequenzen und Proteinensequenzen mittels Massenspektromterie |
| US6640191B1 (en) * | 1999-12-30 | 2003-10-28 | The Regents Of The University Of California | Library design in combinatorial chemistry by Monte Carlo methods |
-
2004
- 2004-06-25 WO PCT/US2004/020059 patent/WO2005001645A2/fr active Application Filing
- 2004-06-25 EP EP04776948A patent/EP1644860A4/fr not_active Withdrawn
Non-Patent Citations (2)
| Title |
|---|
| CAFLISCH A ET AL: "Multiple copy simultaneous search and construction of ligands in binding sites: application to inhibitors of HIV-1 aspartic proteinase.", JOURNAL OF MEDICINAL CHEMISTRY 23 JUL 1993, vol. 36, no. 15, 23 July 1993 (1993-07-23), pages 2142 - 2167, XP002485505, ISSN: 0022-2623 * |
| GUARNIERI F ET AL: "SIMULATED ANNEALING OF CHEMICAL POTENTIAL: A GENERAL PROCEDURE FOR LOCATING BOUND WATERS. APPLICATION TO THE STUDY OF THE DIFFERENTIAL HYDRATION PROPENSITIES FOR THE MAJOR AND MINOR GROOVES OF DNA", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, US, vol. 118, no. 35, 1 January 1996 (1996-01-01), pages 8493/8494, XP009061246, ISSN: 0002-7863 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2005001645A3 (fr) | 2005-04-28 |
| WO2005001645A2 (fr) | 2005-01-06 |
| EP1644860A2 (fr) | 2006-04-12 |
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Legal Events
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| 17P | Request for examination filed |
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| DAX | Request for extension of the european patent (deleted) | ||
| A4 | Supplementary search report drawn up and despatched |
Effective date: 20080709 |
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| RIC1 | Information provided on ipc code assigned before grant |
Ipc: G06F 19/00 20060101AFI20080630BHEP Ipc: G06G 7/48 20060101ALI20080630BHEP |
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| 17Q | First examination report despatched |
Effective date: 20090130 |
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| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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| 18D | Application deemed to be withdrawn |
Effective date: 20090610 |