CN102507883B - Method for predicating novel curative effects of medicament based on biological process and application of method - Google Patents

Abstract

The invention relates to a method for predicating novel curative effects of a medicament based on a biological process, which is disease-oriented and used to predicate a potential novel treating function of the medicament based on a medicament-disease relevance of a biological process spectrum. The method comprises the following steps of: (1) constructing a disease biological process spectrum and a medicament biological process spectrum; (2) calculating medicament-disease relevance scores on the layer of the biological process spectrum; (3) judging the significance of the relevance scores; and (4) screening a medicament-disease relation with the significance and carrying out further experimental demonstration on functions of the medicament by a user according to a sequencing result of the relevance scores. The invention further relates to an application of the method to the predication of the novel curative effects of the medicament. The predication method provided by the invention is ingenious in design, can be used for more comprehensively evaluating the medicament-disease relation, has important meanings of looking for novel medicaments for treating diseases, finding potential toxic or side effects of the medicaments, expanding a treating function space of the traditional medicaments, developing new uses for approved medicaments and the like, and is suitable for being popularized and applied on a large scale.

Description

A kind of method and application based on the new curative effect of bioprocess prediction medicine

Technical field

The present invention relates to curative effect of medication technical field, be particularly related to the new curative effect discovery technique of medicine field, specifically refer to a kind of method and application based on the new curative effect of bioprocess prediction medicine, function to existing medicine is reappraised, thereby find new treatment function or potential spinoff, instruct clinical application and new drug development.

Background technology

New drug development is an excessive risk process extremely taking time and effort.From an active small molecular to its approval listing, on average need 800,000,000 dollars, the cycle is 15 years, nearly 90% active small molecular may will suffer exit in the time of 1 phase clinical trial.In general the main reason that, medicine is eliminated is due to weak curative effect and toxic and side effect.Some medicine is after approval listing, and market survey finds that long-term efficacy is low, or serious toxic and side effect, thereby needs amend the description even to remove city; Also may be in the new therapeutic action of clinical middle discovery medicine.

Although be to increase year by year to the input of new drug development, many high-throughout new technologies are applied in this field, and the output capacity of new drug reached with since a peak except the mid-90 in last century, always all on a declining curve.Thereby, find efficient drug development New Policy or new resources, become the task of top priority.Medicine reorientation (drug repositioning) is widely recognized as one of a kind of effective ways that solve low this predicament of output of new drug development high investment.It is based on the existing new treatment function of drug development, and making full use of " old " medicine has had comparatively complete pharmacokinetics and toxicology information, can carry out the second stage of clinical trial test to new function fast, thereby shortens the construction cycle, reduces risk.

The method of at present common medicine reorientation is mainly that the aspect based on drug-drug relation is predicted new function, relatively typical method has 4 kinds: one, according to Medicine small molecule structural similarity, the existing target spot information of bound drug, infer new target spot (Keiser MJ, Setola V, Irwin JJ, Laggner C, Abbas AI, Hufeisen SJ, Jensen NH, Kuijer MB, MatosRC, Tran TB et al:Predicting new molecular targets for known drugs.Nature 2009, 462 (7270): 175-181).Two, based on spinoff similarity, determine potential drug-drug relation, and then prediction novel targets (Campillos M, Kuhn M, Gavin AC, Jensen LJ, Bork P:Drug target identification using side-effectsimilarity.Science 2008,321 (5886): 263-266).Three, by the correlativity of gene expression profile under medicine irritation, the existing function of bound drug, infer new function (Iorio F, Bosotti R, Scacheri E, Belcastro V, Mithbaokar P, FerrieroR, Murino L, Tagliaferri R, Brunetti-Pierri N, Isacchi A et al:Discovery of drug mode of action anddrug repositioning from transcriptional responses.Proc Natl Acad Sci USA 2010,107 (33): 14621-14626).Four, (the He L such as nearest Heng Luo, Luo H, Chen J, Shi LM, Mikailov M, Zhu H, Wang KJ, Yang L:DRAR-CPI:a server for identifying drug repositioning potential and adversedrug reactions via the chemical-protein interactome.Nucleic Acids Research 2011, 39:W492-W498) a kind of new method is proposed, the CPI (chemical-protein interactome) that utilizes the known drug molecule of molecular docking technique construction function and Drug side reaction albumen, the relatively correlativity of the medicine of query and the CPI of said medicine molecule, predict potential new function.Said method proposes the strategy of the new outcome prediction of medicine based on different angles, what have has even had a successful application case, but " new curative effect " that these methods are found is often limited in the existing functional space of existing medicine, is not suitable for existing medicine and fails the disease for the treatment of.In addition,, for these new curative effects of finding, can not make the quantification sequence of medicine-treatment function interdependency power.

Therefore, how based on existing target spot information, find the object that new method reaches the relation of comparatively comprehensively assessing medicine-disease, for finding the new medicine of disease, find medicine potential toxic and side effect, expand the treatment functional space of existing medicine and " old " medicine newly with etc. have great significance.

Summary of the invention

The object of the invention is to have overcome above-mentioned shortcoming of the prior art, a kind of method and application based on the new curative effect of bioprocess prediction medicine is provided, should the method based on the new curative effect of bioprocess prediction medicine design ingenious, can comparatively comprehensively assess the relation of medicine-disease, for finding the new medicine of disease, the potential toxic and side effect of medicine finds, expand the treatment functional space of existing medicine and " old " medicine newly with etc. have great significance, be suitable for large-scale promotion application.

Bioprocess is the most basic biological function unit of manual annotation, by a histone or a function the most basic of the common enforcement of gene interaction.Bioprocess comprises metabolic pathway, signal path etc.Concrete as bioprocess such as vascular smooth muscle contraction and expansion, cell cycles.

Method based on the new curative effect of bioprocess prediction medicine of the present invention, based on following 3 basic assumptions, is determined a new drug therapy disease model (as shown in Figure 1): 1, drug molecule produces the result for the treatment of to disease by the specific albumen in acting body or nucleic acid conventionally.2, albumen not isolated playing a role in human body, often by with other body in component form albumen composition or bioprocess is exercised its function.3, disease is as a complicated phenotype, often relates to the abnormal of multiple bioprocess in body system.Medicine target may not be disease related protein, but with disease related protein on same bioprocess, medicine can reach the object that regulates this morbid state by impact and the bioprocess of disease association.

The method can make full use of existing medicine target information, and the function (comprising spinoff) that comprehensive assessment medicine is new, has feature accurately and efficiently, can provide guidance for clinical application, as a kind of method of medicine reorientation, can greatly accelerate accelerate development novel drugs simultaneously.

To achieve these goals, in a first aspect of the present invention, provide a kind of method based on the new curative effect of bioprocess prediction medicine, it is characterized in that, comprised the following steps:

(1) build disease bioprocess spectrum and medicine bioprocess spectrum;

(2) in bioprocess spectrum aspect, calculate the relevance score of medicine-disease;

(3) conspicuousness of measurement relevance score;

(4) screening has the medicine-disease relationship of conspicuousness, and user can, according to relevance score ranking results, carry out further experimental demonstration to the function of medicine.

The bioprocess spectrum of medicine, refers to that the target spot of medicine is to the influence degree of each bioprocess.As: in bioprocess A, have 4 albumen, 3 is the medicine target of this medicine; And bioprocess B has 8 albumen, wherein 1 is the medicine target of this medicine, may go out the influence degree of medicine to these two bioprocess by statistical computation so.The bioprocess spectrum here refers to does an evaluation to the bioprocess of all collections.

Preferably, described step (1) specifically comprises the following steps:

(11) build bioprocess data set; Namely collect or integrate existing about bioprocess data.

(12) build disease and disease related protein data set; Namely collect or integrate existing about disease and disease related protein data.

(13) the target spot data based on medicine and bioprocess data set, calculates the influence degree of medicine to bioprocess, obtains the bioprocess spectrum of medicine; Based on disease and disease related protein data set and bioprocess data set, calculate the influence degree of disease to bioprocess, obtain the bioprocess spectrum of disease.

More preferably, in described step (13), adopt Fisher ' s exact test to calculate influence degree and the disease influence degree to bioprocess of medicine to bioprocess.

Preferably, described step (2) specifically comprises the following steps:

(21) choose the bioprocess of medicine, the equal appreciable impact of disease, in bioprocess spectrum aspect, calculate the relevance score of medicine-disease.

More preferably, in described step (21), adopt the product of the influence degree of medicine to bioprocess and the influence degree of disease to bioprocess to add and calculate the relevance score of medicine-disease, see following formula (I):

$S_{\mathrm{drug},\mathrm{diseasei}}=-\mathrm{lg\Σ}\sqrt{p_{\mathrm{drug},k}\×p_{\mathrm{diseasei},k}}---\left(I\right),$

Wherein S _{drug, disease i}: the relevance score of medicine-disease i; p _{drug, k}: the p value of the enrichment of medicine on bioprocess k; p _{disease i, k}: the p value of the enrichment of disease i on bioprocess k; K: disease i and medicine be the bioprocess of appreciable impact all.

Preferably, described step (3) specifically comprises the following steps:

(31) build the random bioprocess spectrum of medicine;

(32) distribution situation of the relevance score of the random bioprocess spectrum of calculating medicine and disease, whether the relevance score of statistical test medicine-disease is significantly higher than stochastic distribution.

More preferably, in described step (32), whether the relevance score of weighing medicine-disease by calculating Z-score has conspicuousness:

$z-{\mathrm{score}}_{\mathrm{drug},\mathrm{diseasei}}=\frac{S_{\mathrm{drug},\mathrm{diseasei}}-\mathrm{average}\left(S_{\mathrm{random},\mathrm{diseasei}}\right)}{\mathrm{std}\left(S_{\mathrm{random},\mathrm{diseasei}}\right)}$

Wherein S _{drug, disease i}: the relevance score of medicine-disease i; Average (S _{random, disease i}): the relevance average of the random bioprocess spectrum of medicine and disease i; Std (S _{random, disease i}): the relevance standard deviation of the random bioprocess spectrum of medicine and disease i.

In a second aspect of the present invention, provide the application of the above-mentioned method based on the new curative effect of bioprocess prediction medicine in the new curative effect of prediction medicine.

Beneficial effect of the present invention is specifically:

1, the relevance that the present invention is based on bioprocess spectrum is predicted the treatment function (spectrum of disease) that medicine is possible, take full advantage of the existing target spot information of medicine, and consider bioprocess this feature of carrier as albumen practical function, medicine may not act directly on disease related protein, but be in identical biological pathway with it, produce result for the treatment of.Compare other method, this disease is the method for guiding, is not subject to the restriction in the pharmacological function space of existing medicine, more trends towards the pharmacological function spectrum of just evaluation medicine, finds the new function of medicine.For newfound treatment function, confirm by further clinical trial, can expand the functional space of existing medicine.And for potential spinoff, the side effects of pharmaceutical drugs assessment of instructing that can be directed is tested, for clinical safe medication provides safeguard.

2, the present invention has examined or check the relation of the bioprocess of medicine effect and the bioprocess of sickness influence comprehensively, and the biological pathway at the place of target spot targetedly while being not only drug design, disease often relates to the abnormal of multiple bioprocess as a complicated phenotype, and therefore the method is likely found the therapeutic strategy that disease is new.

3, the present invention is the relevance of examining or check medicine and disease in bioprocess aspect, and this makes directly to utilize transcription group data (without obtaining drug target through a large amount of meticulous experiments) to predict that the pharmacological function (spectrum of disease) of active small molecular becomes possibility.

Brief description of the drawings

Fig. 1 is the schematic diagram for the drug therapy disease model of the method based on the new curative effect of bioprocess prediction medicine of the present invention.

Fig. 2 is the process flow diagram that adopts the new curative effect of method prediction medicine based on the new curative effect of bioprocess prediction medicine of the present invention, pharmaceutically-active target spot has multiple, pass through statistical calculations, can obtain the influence degree of these target spots to each bioprocess, p1 in figure, p2..pn represents that respectively medicine is to bioprocess 1, the influence degree of bioprocess 2... bioprocess n, one group of p1, the vector of p2....pn composition is referred to as the bioprocess spectrum of medicine.

Embodiment

In order more clearly to understand technology contents of the present invention, describe the present invention below in conjunction with Fig. 2.Should be understood that embodiment is only for the present invention is described, instead of limitation of the present invention.

(1) build bioprocess data set; According to the statistical information of Pathguide (URL:http: //www.pathguide.org/), present stage has the nearly bioprocess database of 325, relatively more typical in KEGG, Biocarta database, Reactome, PID, GO etc.User can select specifically to count source, storehouse as required, or integrates multiple Data Sources.

(2) build disease and disease related protein data set

Find disease related protein, the biomarker of disease or the research of Disease-causing gene is one of popular direction of biomedicine field always.The data of disease related protein are mainly distributed in the albumen Relational database of arrangement and the biological medicine document of magnanimity at present.Conventional common data base comprises OMIM (URL:http: //www.ncbi.nlm.nih.gov/omim/), CGAP (URL:http: //cgap.nci.nih.gov/), GeneCards (URL:http: //www.genecards.org/), TGDB (URL:http: //www.tumor-gene.org/), Comparative Toxicogenomics Database (URL:http: //ctd.mdibl.org/), HuGE Navigator (URL:http: //www.hugenavigator.net/), ATLAS of Geneticsand Cytogenetics in Oncology and Haematology (URL:http: //atlasgeneticsoncology.org) and be scattered in a large number the disease-albumen relation in scientific literature.Omim database has been collected existing human inheritance's class disease and corresponding Disease-causing gene information, has collected the information such as pathologic process associated protein or biological marker of the disease of experimental verification in CTD database.Uniprot collects this part information equally as comprehensive albumen database.In the present invention, integrate outside above-mentioned multiple common data base, also include and adopted this to organize independently developed disease-albumen database (http://lifecenter.sgst.cn/ddpa/), and disease-albumen relation (the Li Y of third party based on the arrangement of the text method of excavation, Agarwal P:A pathway-based view of human diseasesand disease relationships.PLoS One 2009,4 (2): e4346.) disease of, collecting based on Text Mining Technology is with disease related protein information.

(3) structure of the bioprocess spectrum that disease affects

The method that builds bioprocess spectrum has a lot of methods (common as Fisher ' s exact test, hypergeom test, GASE etc.), choose wherein any one, calculate the influence degree of disease related protein at each bioprocess, system is stored in the bioprocess of the impact of each disease spectrum on backstage.

The structure of the bioprocess spectrum of medicine to be measured

User can be by retrieval drug target database, and as the difference expression gene under the database such as DrugBank, TTD or submission medicine irritation, construction method builds with the bioprocess spectrum of disease.

(4) medicine to be measured and disease association marking.

The being connected property scoring method of the bioprocess spectrum of two kinds of different angles is provided in the present invention, has selected for user.

1, the influence degree to each bioprocess according to medicine/disease, whether examination p value is lower than the upper conspicuousness threshold value of statistics, thereby the bioprocess spectrum fingerprint that changes into 0-1 vector composition, expression medicine/disease that assignment is 1 has impact to this bioprocess.Copy Tanimoto coefficient (Willett P, Barnard JM, Downs GM:Chemical similarity searching.J ChemInf Comp Sci 1998,38 (6): 983-996.) computing method, the correlativity of examination medicine and each disease.

2, choose all bioprocess of energy appreciable impact of medicine/disease with 1, directly add and give a mark as both relevances at the product of the influence degree of each bioprocess according to medicine/disease, specifically refer to formula (I):

$S_{\mathrm{drug},\mathrm{diseasei}}=-\mathrm{lg\Σ}\sqrt{p_{\mathrm{drug},k}\×p_{\mathrm{diseasei},k}}---\left(I\right),$

Wherein S _{drug, disease i}: the relevance score of medicine-disease i; p _{drug, k}: the p value of the enrichment of medicine on bioprocess k; p _{disease i, k}: the p value of the enrichment of disease i on bioprocess k; K: disease i and medicine be the bioprocess of appreciable impact all.

(5) Evaluation on specificity of medicine to be measured and disease association score.

1, keep the bioprocess spectral sequence of medicine constant, upset at random bioprocess title and obtain for 100,000 times the random bioprocess spectrum of medicine.Calculate the relevance score of each random bioprocess spectrum and disease according to step (three), obtain the stochastic distribution of medicine-disease association score.

2, calculate Z-score measurement medicine whether the relevance of this disease is had to conspicuousness.

$z-{\mathrm{score}}_{\mathrm{drug},\mathrm{diseasei}}=\frac{S_{\mathrm{drug},\mathrm{diseasei}}-\mathrm{average}\left(S_{\mathrm{random},\mathrm{diseasei}}\right)}{\mathrm{std}\left(S_{\mathrm{random},\mathrm{diseasei}}\right)}$

Wherein S _{drug, disease i}: the relevance score of medicine-disease i; Average (S _{random, disease i}): the relevance average of the random bioprocess spectrum of medicine and disease i; Std (S _{random, disease i}): the relevance standard deviation of the random bioprocess spectrum of medicine and disease i.

(6) according to medicine-disease association score, descending sort from high to low, the higher explanation medicine of score value is stronger on the impact of this disease.User can choose the result that score value is higher, and the new function of medicine is carried out to further experimental demonstration.

the evaluation of the accuracy of the method based on the new curative effect of bioprocess prediction medicine

In the present invention, adopting the most fast-selling target spot medicine more than 8 in the whole world in 2010 is Etanercept, Bevacizumab, Aripiprazole, Rituximab, Adalimumab, Quetiapine, Trastuzumab, Olanzapine evaluates the accuracy of method as test set.On the whole, in 8 fast-selling medicines having tested, the position that cures mainly function and all come Top 10 of FDA approval, and the new function of predicting in addition, what have directly clinical or document evidence support on average accounts for 60%, this predicting the outcome of the method for explanation has certain confidence level, for there is no at present bibliographical information, is probably medicine potential new treatment function or undiscovered toxic and side effect still.These 8 medicines are roughly divided into 3 classes, treat the medicine of mental disease, treatment quasi-moisture arthritis and treatment cancer.Here respectively choosing a kind of medicine discusses in detail.The test process of other 5 kinds of medicines is similar, and when difference is to build the bioprocess spectrum of medicine, method, with example 1 and example 2, just finds the albumen target spot of different pharmaceutical in DrugBank database, and encloses and predict the outcome.

Example 1:

Etanercept (Etanercept, commodity are called Enbrel) is the recombinant protein medicine of the combination TNF of U.S. Amgenc and the exploitation of Pfizer company, and its approval indication is rheumatoid arthritis.DrugBank database has been included 14 target spots of its effect.

Build bioprocess data set; Adopt pathway information in KEGG as bioprocess data set, 183 bioprocess altogether.

Build disease and disease related protein data set; (in CTD (http://ctd.mdibl.org/) database, be labeled as disease and the disease related protein of " curated ", and the independently developed DDPA database of seminar (http://lifecenter.sgst.cn/ddpa/), altogether comprise 1101 kinds of diseases, 5898 disease related proteins).

The structure of the bioprocess spectrum of disease

Based on disease and the disease related protein data of collecting, adopt Fisher ' s exact test statistical model, calculate the influence degree of 183 bioprocess that disease collects, obtain 1101 diseases special bioprocess spectrum separately.

The bioprocess spectrum of Etanercept builds

Inquiry DrugBank (http://drugbank.ca/) database obtains 14 target spots of Etanercept, adopts Fisher ' s exact test to calculate the influence degree of Etanercept to 183 bioprocess, obtains the bioprocess spectrum of Etanercept.

Calculate the relevance score of Etanercept and each disease:

$S_{\mathrm{drug},\mathrm{diseasei}}=-\mathrm{lg\Σ}\sqrt{p_{\mathrm{drug},k}\×p_{\mathrm{diseasei},k}}---\left(I\right),$

Wherein S _{drug, disease i}: the relevance score of medicine-disease i; p _{drug, k}: the p value of the enrichment of medicine on bioprocess k; p _{disease i, k}: the p value of the enrichment of disease i on bioprocess k; K: disease i and medicine be the bioprocess of appreciable impact all.

Build the random bioprocess spectrum of Etanercept:

Keep the sequence of values in the bioprocess spectrum of Etanercept constant, bother at random the title 1,00000 time of bioprocess spectrum, obtain 1,00000 random bioprocess spectrum.Upset number of times generally at 100,000-1,000,000 time just passable.

Random bioprocess spectrum and the relevance of each disease of Etanercept are calculated, and calculate the relevance score of the random bioprocess spectrum of each Etanercept and disease by formula (I).

Weigh the conspicuousness of Etanercept-disease association score.Adopt following formula to weigh:

$z-{\mathrm{score}}_{\mathrm{drug},\mathrm{diseasei}}=\frac{S_{\mathrm{drug},\mathrm{diseasei}}-\mathrm{average}\left(S_{\mathrm{random},\mathrm{diseasei}}\right)}{\mathrm{std}\left(S_{\mathrm{random},\mathrm{diseasei}}\right)}$

Wherein S _{drug, disease i}: the relevance score of medicine-disease i; Average (S _{random, disease i}): the relevance average of the random bioprocess spectrum of medicine and disease i; Std (S _{random, disease i}): the relevance standard deviation of the random bioprocess spectrum of medicine and disease i.

For the Etanercept-disease relationship that has conspicuousness, according to score sequence, what choose here is that score is the highest and have front 10 results of conspicuousness.

The Etanercept associated disease forecasting (TOP 10) of table 1. based on bioprocess spectrum

What & FDA ratified cures mainly function

* document support

That in upper table, can see in predicting the outcome directly document support has 5, and this medicine of FDA approval cure mainly disease rheumatoid arthritis (Arthritis, Rheumatoid) make number one, at present be also contained in (Feldman SR in result in the Psoriasis of three phase clinical stages, Kimball AB, Krueger GG, Woolley JM, Lalla D, Jahreis A:Etanercept improvesthe health-related quality of life of patients with psoriasis:results of a phase III randomized clinicaltrial.J Am Acad Dermatol 2005, 53 (5): 887-889.).For periodontitis (Periodontitis), point out that Etanercept can treat this disease although also there is no the experiment of special clinical medicine, but the rheumatoid arthritis curing mainly of periodontitis and Etanercept belongs to chronic inflammation class disease, they have a lot of identical risks and assumptions and pathology path, periodontitis may be to the latter's pathology generation important (de Smit MJ, Brouwer E, Vissink A, van Winkelhoff AJ:Rheumatoidarthritis and periodontitis; A possible link via citrullination.Anaerobe 2011.), and find on epidemiology, rheumatoid arthritis patients occurs that the probability of periodontitis is ordinary people's twice (Berthelot JM, Le Goff B:Rheumatoidarthritis and periodontal disease.Joint Bone Spine 2010,77 (6): 537-541.).In addition, (the DiPaola R such as Di Paola R, Mazzon E, Muia C, Crisafulli C, Terrana D, Greco S, Britti D, Santori D, Oteri G, Cordasco G et al:Effects of etanercept, a tumour necrosis factor-alpha antagonist, in anexperimental model of periodontitis in rats.Br J Pharmacol 2007, 150 (3): 286-297.) on the rat model of periodontitis, confirm Etanercept amelioration of inflammation generation effectively, the relevant symptoms such as tissue injury.Systemic loupus erythematosus (LupusErythematosus, Systemic) as a kind of general autoimmunity disease of invading skin and many internal organs, the antagonist (comprising Etanercept) of TNF-alpha has been proved in multiple research can induce its pathology that (Swale VJ occurs, Perrett CM, Denton CP, Black CM, Rustin MH:Etanercept-induced systemic lupus erythematosus.Clin Exp Dermatol 2003,28 (6): 604-607.; Kang MJ, Lee YH, Lee J:Etanercept-induced systemic lupus erythematosus in apatient with rheumatoid arthritis.J Korean Med Sci 2006,21 (5): 946-949.; Shakoor N, Michalska M, Harris CA, Block JA:Drug-induced systemic lupus erythematosus associated with etanercepttherapy.Lancet 2002,359 (9306): 579-580.).TNF-alpha is as the important albumen of breast cancer disease reason generating process, (the Madhusudan S such as Madhusudan S, Foster M, Muthuramalingam SR, Braybrooke JP, Wilner S, KaurK, Han C, Hoare S, Balkwill F, Talbot DC et al:A phase II study of etanercept (Enbrel), a tumornecrosis factor alpha inhibitor in patients with metastatic breast cancer.Clin Cancer Res 2004, 10 (19): 6528-6534.) in the second stage of clinical trial of 16 samples, confirm its symptom of improving that Etanercept can be effective and safe.Incubation period solubility TNF-R1; the rising of TNF-R2 level is normal conceived important symbol; habitual abortion (Abortion; Habitual) pregnant woman does not have this phenomenon (Chernyshov VP; Vodyanik MA; Pisareva SP:Lack ofsoluble TNF-receptors in women with recurrent spontaneous abortion and possibility for itscorrection.Am J Reprod Immunol 2005,54 (5): 284-291.).(the Winger EE such as Winger EE, Reed JL:Treatment with tumor necrosis factor inhibitors and intravenous immunoglobulin improves livebirth rates in women with recurrent spontaneous abortion.Am J Reprod Immunol 2008,60 (1): 8-16.) confirm that the inhibitor of TNF-alpha and intravenous immunoglobulin (Ig) can improve live birth rate in the clinical trial of pregnant woman's sample of 75 habitual abortions.

Lymphocytic choriomeningitis (Lymphocytic Choriomeningitis), glioblastoma (Glioblastoma), osteopetrosis (Osteopetrosis), these 4 kinds of diseases of malaria (malaria), although directly not experimental results show that in document what impact etanercept has to them, but, from document, still can find some valuable clues.

For lymphocytic choriomeningitis, from predicting the outcome, Etanercept is mainly from 4 path Hematopoietic cell lineage, NOD-like receptor signaling bioprocess, Natural killer cell mediatedcytotoxicity, Adipocytokine signaling pathway, Osteoclast differentiation affects lymphocytic choriomeningitis.(the Rodas JD such as Rodas JD, Cairo C, Djavani M, Zapata JC, Ruckwardt T, Bryant J, PauzaCD, Lukashevich IS, Salvato MS:Circulating natural killer and gammadelta T cells decrease soonafter infection of rhesus macaques with lymphocytic choriomeningitis virus.Mem Inst OswaldoCruz 2009,104 (4): 583-591.) on the lymphocytic of rhesus macaque choriomeningitis virus model, find to infect the natural killer cell minimizing that lymphocytic choriomeningitis can cause circulation, and (the WallaceDJ:The use of etanercept and other tumor necrosis factor-alpha blockers in infertility:it ' s time toget serious.J Rheumatol 2003 such as DANIEL J.WALLACE, 30 (9): 1897-1899.) confirm that etanercept can reduce the level of NK cell, therefore natural killer cell mediated cytotoxicity path is likely that etanercept affects one of reason of lymphocytic choriomeningitis.

TNF-alpha is as important cancer associated protein, can induce glioblastoma cell medium vessels to generate high expressed (the Nabors LB of the factor, Suswam E, Huang Y, Yang X, Johnson MJ, King PH:Tumor necrosis factor alphainduces angiogenic factor up-regulation in malignant glioma cells:a role for RNA stabilization andHuR.Cancer Res 2003,63 (14): 4181-4187.).Be not difficult to infer in conjunction with the design original intention of etanercept, it may have certain therapeutic action to glioblastoma.Osteopetrosis is to weigh unbalance caused disease (the Lazner F of absorption process because the bone of Gegenbaur's cell (osteoblast) mediation forms with the bone of osteoclast (osteoclast) mediation, Gowen M, Pavasovic D, Kola I:Osteopetrosis and osteoporosis:two sides of the same coin.Hum Mol Genet 1999,8 (10): 1839-1846.).Clinical trial evidence shows TNF-alpha (the Boyce BF that all plays an important role in the pathologic process of various forms of bone-loss, Li P, Yao Z, Zhang Q, Badell IR, Schwarz EM, O ' Keefe RJ, Xing L:TNF-alpha and pathologic bone resorption.Keio J Med 2005,54 (3): 127-131.).In conjunction with predicting the outcome, be likely by Osteoclast differentiation path and affect osteopetrosis as the etanercept of the monoclonal antibody of TNF-alpha.

Malaria is to infect the caused insect-borne infectious disease of plasmodium through mosquito bite.(the Depinay N such as Depinay N, Franetich JF, Gruner AC, Mauduit M, Chavatte JM, Luty AJ, van Gemert GJ, Sauerwein RW, Siksik JM, Hannoun L et al:Inhibitory effect of TNF-alpha on malaria pre-erythrocytic stage development:influence of host hepatocyte/parasite combinations.PLoS One 2011, 6 (3): e17464.) TNF-alpha that has tested in vitro people and mouse is to Infected With Plasmodium liver cell, the impact of hepatoma carcinoma cell, find that TNF-alpha can suppress this course of infection, therefore, can infer that etanercept may strengthen plasmodial infection risk as the inhibitor of TNF-alpha.

Example 2:

Aripiprazole (Aripiprazole, commodity are called Abilify) be in the third generation atypical antipsychotic agents of approval listing on November 15th, 2002 by U.S. FDA, the Dopamine receptor D2 activator that belongs to qualone derivative class, is mainly used in treating schizophrenia.25 action target spots altogether in DrugBank database, are included.

Build bioprocess data set; Adopt the pathway information except disease type in KEGG (http://www.genome.jp/kegg/) as bioprocess data set, 183 bioprocess altogether.

Build disease and disease related protein data set; (in CTD (http://ctd.mdibl.org/) database, be labeled as disease and the disease related protein of " curated ", and the independently developed DDPA database of seminar (http://lifecenter.sgst.cn/ddpa/), altogether comprise 1101 kinds of diseases, 5898 disease related proteins).

The structure of the bioprocess spectrum of disease

Based on disease and the disease related protein data of collecting, adopt Fisher ' s exact test statistical model, calculate the influence degree of 183 bioprocess that disease collects, obtain 1101 diseases special bioprocess spectrum separately.

The bioprocess spectrum of Aripiprazole builds

Inquiry DrugBank (http://drugbank.ca/) database obtains 25 target spots of Aripiprazole, adopts Fisher ' s exact test to calculate the influence degree of Aripiprazole to 183 bioprocess, obtains the bioprocess spectrum of Aripiprazole.

Calculate the relevance score of Aripiprazole and each disease:

$S_{\mathrm{drug},\mathrm{diseasei}}=-\mathrm{lg\Σ}\sqrt{p_{\mathrm{drug},k}\×p_{\mathrm{diseasei},k}}---\left(I\right),$

Wherein S _{drug, disease i}: the relevance score of medicine-disease i; p _{drug, k}: the p value of the enrichment of medicine on bioprocess k; p _{disease i, k}: the p value of the enrichment of disease i on bioprocess k; K: disease i and medicine be the bioprocess of appreciable impact all.

Build the random bioprocess spectrum of Aripiprazole:

Keep the sequence of values in the raw process spectrum of Aripiprazole constant, bother at random the title 1,00000 time of bioprocess spectrum, obtain 1,00000 random bioprocess spectrum.Upset number of times generally at 100,000-1,000,000 time just passable.

Random bioprocess spectrum and the relevance of each disease of Aripiprazole are calculated, and calculate the relevance score of the random bioprocess spectrum of each Aripiprazole and disease by formula (I).

Weigh the conspicuousness of Aripiprazole-disease association score.Adopt following formula to weigh:

$z-{\mathrm{score}}_{\mathrm{drug},\mathrm{diseasei}}=\frac{S_{\mathrm{drug},\mathrm{diseasei}}-\mathrm{average}\left(S_{\mathrm{random},\mathrm{diseasei}}\right)}{\mathrm{std}\left(S_{\mathrm{random},\mathrm{diseasei}}\right)}$

Wherein S _{drug, disease i}: the relevance score of medicine-disease i; Average (S _{random, disease i}): the relevance average of the random bioprocess spectrum of medicine and disease i; Std (S _{random, disease i}): the relevance standard deviation of the random bioprocess spectrum of medicine and disease i.

For the Aripiprazole-disease relationship that has conspicuousness, according to score sequence, what choose here is that score is the highest and have front 10 results of conspicuousness.

The Aripiprazole associated disease forecasting (TOP 10) of table 2. based on bioprocess spectrum

What & FDA ratified cures mainly function

* document support

10 diseases in upper table, comprise 4 kinds of mental diseases, are respectively Schizophrenia, Bipolar Disorder, AutisticDisorder, Attention Deficit Disorder with Hyperactivity.Wherein the above two are all the functions that cures mainly of FDA approval.Although Aripiprazole treatment self-closing disease (Autistic Disorder) does not have FDA official approval, but as atypical chlorpromazine, had in recent years lot of documents report its in clinical for (the Erickson CA of the treatment to this disease, Stigler KA, PoseyDJ, McDougle CJ:Aripiprazole in autism spectrum disorders and fragile X syndrome.Neurotherapeutics 2010,7 (3): 258-263.; Pardini M, Guida S, Gialloreti LE:Aripiprazole treatmentfor coprophagia in autistic disorder.J Neuropsychiatry Clin Neurosci 2010,22 (4): 451-s e433-451e433.; Blankenship K, Erickson CA, Stigler KA, Posey DJ, McDougle CJ:Aripiprazole forirritability associated with autistic disorder in children and adolescents aged 6-17 years.Ped Health2010,4 (4): 375-381.).For attention deficit hyperactivity disorder (Attention Deficit Disorder with Hyperactivity), existing clinical small sample experiment confirms, Aripiprazole can effectively be alleviated this sick symptom of children, and to recognizing ability (the Findling RL that is free from side effects, Short EJ, Leskovec T, Townsend LD, Demeter CA, McNamara NK, Stansbrey RJ:Aripiprazole in children with attention-deficit/hyperactivity disorder.Journal of child andadolescent psychopharmacology 2008, 18 (4): 347-354.).In addition, for the common spinoff of the instructions of this medicine as fat (Obesity), diabetes (Diabetes Mellitus, Experimental), epilepsy (Epilepsy, Generalized), has also obtained good prediction here.The activation of dopaminergic system (Del Zompo M:Dopaminergic hypersensitivity in migraine:clinical and geneticevidence.Funct Neurol 2000, the 15 Suppl 3:163-170. that play an important role in the pathology evolution of migraines (Migraine Disorders), Cubo E, Kompoliti K, Leurgans SE, Raman R:Dopaminergic hypersensitivity in patients with Parkinson disease and migraine.ClinNeuropharmacol 2004, 27 (1): 30-32.), and the aripiprazole activator of Dopamine receptor D2 in this system just, LaPorta LD (LaPorta LD:Relief from migraine headache with aripiprazole treatment.Headache2007, 47 (6): 922-926.) in three clinical cases, find that aripiprazole treats the state that can alleviate migraines.In addition, many clinical researches show that aripiprazole can cause dysfunction (Dyskinesia, Drug-Induced) (Maytal G, Ostacher M, Stern TA:Aripiprazole-related tardive dyskinesia.CNS Spectr 2006,11 (6): 435-439.; Abbasian C, Power P:A case of aripiprazole and tardive dyskinesia.J Psychopharmacol 2009,23 (2): 214-215.; Pena MS, Yaltho TC, Jankovic J:Tardive dyskinesia and other movement disorders secondary toaripiprazole.Mov Disord 2011,26 (1): 147-152.).For cerebral anoxia (Hypoxia, Brain) damage causing, in document, report calcium channel to cerebral anoxia early stage caused neurotrosis (the Schurr A:Neuroprotectionagainst ischemic/hypoxic brain damage:blockers of ionotropic glutamate receptor and voltagesensitive calcium channels.Curr Drug Targets 2004 that plays an important role, 5 (7): 603-618.), and Aripiprazole energy effective influence Calcium signaling path (Zhang JY, Kowal DM, Nawoschik SP, Lou Z, Dunlop J:Distinct functionalprofiles of aripiprazole and olanzapine at RNA edited human 5-HT2C receptor isoforms.BiochemPharmacol 2006,71 (4): 521-529.), both contact and likely make Aripiprazole produce certain impact to the damage of cerebral anoxia on this path.

Example 3:

Trastuzumab (Trastuzumab, commodity are called Herceptin) is the breast cancer monoclonal antibody drug being positive for HER-2 of company limited of Roche Group exploitation.In DrugBank database, collect the target spot of primary treatment target spot HER-2 and 12 unknown function.

Build bioprocess data set; Adopt the pathway information except disease type in KEGG (http://www.genome.jp/kegg/) as bioprocess data set, 183 bioprocess altogether.

Build disease and disease related protein data set; (in CTD (http://ctd.mdibl.org/) database, be labeled as disease and the disease related protein of " curated ", and the independently developed DDPA database of seminar (http://lifecenter.sgst.cn/ddpa/), altogether comprise 1101 kinds of diseases, 5898 disease related proteins).

The structure of the bioprocess spectrum of disease

Based on disease and the disease related protein data of collecting, adopt Fisher ' s exact test statistical model, calculate the influence degree of 183 bioprocess that disease collects, obtain 1101 diseases special bioprocess spectrum separately.

The bioprocess spectrum of Trastuzumab builds

Inquiry DrugBank (http://drugbank.ca/) database obtains 13 target spots of Trastuzumab, adopts Fisher ' s exact test to calculate the influence degree of Trastuzumab to 183 bioprocess, obtains the bioprocess spectrum of Trastuzumab.

Calculate the relevance score of Trastuzumab and each disease:

$S_{\mathrm{drug},\mathrm{diseasei}}=-\mathrm{lg\Σ}\sqrt{p_{\mathrm{drug},k}\×p_{\mathrm{diseasei},k}}---\left(I\right),$

Wherein S _{drug, disease i}: the relevance score of medicine-disease i; p _{drug, k}: the p value of the enrichment of medicine on bioprocess k; p _{disease i, k}: the p value of the enrichment of disease i on bioprocess k; K: disease i and medicine be the bioprocess of appreciable impact all.

Build the random bioprocess spectrum of Trastuzumab:

Keep the sequence of values in the raw process spectrum of Trastuzumab constant, bother at random the title 1,00000 time of bioprocess spectrum, obtain 1,00000 random bioprocess spectrum.Upset number of times generally at 100,000-1,000,000 time just passable.

Random bioprocess spectrum and the relevance of each disease of Trastuzumab are calculated, and calculate the relevance score of the random bioprocess spectrum of each Trastuzumab and disease by formula (I).

Weigh the conspicuousness of Trastuzumab-disease association score.Adopt following formula to weigh:

$z-{\mathrm{score}}_{\mathrm{drug},\mathrm{diseasei}}=\frac{S_{\mathrm{drug},\mathrm{diseasei}}-\mathrm{average}\left(S_{\mathrm{random},\mathrm{diseasei}}\right)}{\mathrm{std}\left(S_{\mathrm{random},\mathrm{diseasei}}\right)}$

Wherein S _{drug, disease i}: the relevance score of medicine-disease i; Average (S _{random, disease i}): the relevance average of the random bioprocess spectrum of medicine and disease i; Std (S _{random, disease i}): the relevance standard deviation of the random bioprocess spectrum of medicine and disease i.

For the Trastuzumab-disease relationship that has conspicuousness, according to score sequence, what choose here is that score is the highest and have front 10 results of conspicuousness.

The Trastuzumab associated disease forecasting (TOP 10) of table 3. based on bioprocess spectrum

What & FDA ratified cures mainly function

* document support

In upper table, can find out, come in the disease of first 10 except comprising its breast cancer curing mainly, also have other 4 kinds of cancers, respectively: oophoroma (Ovarian Neoplasms), glioblastoma (Glioblastoma), head and neck cancer (Head and NeckNeoplasms), cancer of the stomach (Stomach Neoplasms).From existing reported in literature, the pathologic process of these cancers all relates to ErbB signaling pathway (Maihle NJ, Baron AT, Barrette BA, Boardman CH, Christensen TA, CoraEM, Faupel-Badger JM, Greenwood T, Juneja SC, Lafky JM et al:EGF/ErbB receptor family inovarian cancer.Cancer Treat Res 2002,107:247-258.; Andersson U, Schwartzbaum J, Wiklund F, Sjostrom S, Liu Y, Tsavachidis S, Ahlbom A, Auvinen A, Collatz-Laier H, Feychting M et al:Acomprehensive study of the association between the EGFR and ERBB2 genes and glioma risk.ActaOncol 2010,49 (6): 767-775.; Ratushny V, Astsaturov I, Burtness BA, Golemis EA, Silverman JS:Targeting EGFR resistance networks in head and neck cancer.Cell Signal 2009,21 (8): 1255-1268.; Begnami MD, Fukuda E, Fregnani JH, Nonogaki S, Montagnini AL, da Costa WL, Jr., Soares FA:Prognostic Implications of Altered Human Epidermal Growth Factor Receptors (HERs) in GastricCarcinomas:HER2 and HER3 Are Predictors of Poor Outcome.J Clin Oncol 2011.), and HER-2 in this path just Trastuzumab designed for treatment target.In the clinical pharmacology experiment to these four kinds of cancers, (the Delord JP such as DelordJP, Quideau S, Rochaix P, Caselles O, Couderc B, Hennebelle I, Courbon F, Canal P, Allal BC:Trastuzumab induced in vivo tissue remodelling associated in vitro withinhibition of the active forms of AKT and PTEN and RhoB induction in an ovarian carcinomamodel.Br J Cancer 2010, 103 (1): 61-72.) even if having found that Trastuzumab does not have at HER-2 also may be by suppressing RhoB in the ovarian cancer cell of high expressed, the albumen such as PTEN reach ovarian cancer resistance object.Trastuzumab can be induced A172, the apoptosis of multiple human malignant glioma cell line such as U251 and depend on HER-2 express Cytotoxic generation (Mineo JF, Bordron A, Quintin-Roue I, Loisel S, Ster KL, Buhe V, Lagarde N, Berthou C:Recombinant humanisedanti-HER2/neu antibody (Herceptin) induces cellular death of glioblastomas.Br J Cancer2004,91 (6): 1195-1199.).Simultaneously, Trastuzumab also finds to significantly improve inhibition (the Kondo N of gefitinib to SCCHN, Ishiguro Y, Kimura M, Sano D, Fujita K, Sakakibara A, Taguchi T, Toth G, Matsuda H, Tsukuda M:Antitumor effect of gefitinib on head and neck squamous cellcarcinoma enhanced by trastuzumab.Oncol Rep 2008,20 (2): 373-378.).According to the three phases clinical trial that relates to 24 national crowds of ToGA trial, show that Trastuzumab can effectively extend cancer of the stomach survival rate (the Albarello L that HER-2 is positive, Pecciarini L, Doglioni C:HER2 testing in gastric cancer.Adv Anat Pathol 2011,18 (1): 53-59.).In addition, in a large amount of cytologic experiments, prove HER-2 high expressed in the non-small cell lung cancer cell of (20%-66%), and Trastuzumab can effectively suppress growth (the Azzoli CG of cell, Krug LM, Miller VA, Kris MG, Mass R:Trastuzumab in the treatment of non-small cell lung cancer.Semin Oncol 2002,29 (1 Suppl4): 59-65.; Langer CJ, Stephenson P, Thor A, Vangel M, Johnson DH:Trastuzumab in the treatmentof advanced non-small-cell lung cancer:is there a role? Focus on Eastern Cooperative OncologyGroup study 2598.J Clin Oncol 2004,22 (7): 1180-1187.; Ferrone M, Motl SE:Trastuzumab for thetreatment of non-small-cell lung cancer.Ann Pharmacother 2003,37 (12): 1904-1908.).

Septicemia (Sepsis) is as blood infection class disease, (the John J such as John J, Woodward DB, Wang Y, Yan SB, Fisher D, Kinasewitz GT, Heiselman D:Troponin-I as a prognosticator of mortality in severesepsis patients.J Crit Care 2010,25 (2): 270-275.) sample based on 598 septicemia patients, find that Troponin-I albumen is at the positive correlation that has been in a bad way, concentration is higher, and septicemic cemia mortality ratio is also higher.Simultaneously, in clinical trial, confirm that patient is at level rising (the Telli ML that accepts can cause after Trastuzumab treatment Troponin-I albumen, WittelesRM:Trastuzumab-related cardiac dysfunction.J Natl Compr Canc Netw 2011,9 (2): 243-249.).Based on this, can infer that Trastuzumab may have potential infection septicemia risk.Rheumatoid arthritis (Arthritis, Rheumatoid) be the chronic inflammation class disease of system, react as principal character (Gay S taking synovial tissue's hyperplasia and abnormal immune, Gay RE, Koopman WJ:Molecular and cellular mechanisms of joint destruction inrheumatoid arthritis:two cellular mechanisms explain joint destruction? Ann Rheum Dis 1993,52 Suppl 1:S39-47.).(the Satoh K such as Satoh K, Kikuchi S, Sekimata M, Kabuyama Y, Homma MK, Homma Y:Involvement of ErbB-2 in rheumatoid synovial cell growth.Arthritis Rheum 2001,44 (2): 260-265.) find that ErbB-2 has participated in the breeding of periosteum cell, and this process can suppress by Trastuzumab, this experiment provides new visual angle for treatment rheumatoid arthritis.Systemic loupus erythematosus (Lupus Erythematosus, Systemic) be a class general autoimmunity class disease, wherein Fc-gamma receptor (the Manger K that plays an important role in this sick therapeutic process, Repp R, Jansen M, Geisselbrecht M, Wassmuth R, Westerdaal NA, Pfahlberg A, Manger B, Kalden JR, van de Winkel JG:Fcgamma receptor IIa, IIIa, and IIIb polymorphisms inGerman patients with systemic lupus erythematosus:association with clinical symptoms.AnnRheum Dis 2002, 61 (9): 786-792., Brambila-Tapia AJ, Davalos-Rodriguez IP:[Fcgamma receptorpolymorphisms and systemic lupus erythematosus] .Rev Invest Clin 2009, 61 (1): 66-72.), much research also shows that periodontitis (Periodontitis) and the polymorphism of Fc-gamma receptor have obvious correlativity (Wolf DL, Neiderud AM, Hinckley K, Dahlen G, van de Winkel JG, Papapanou PN:Fcgamma receptorpolymorphisms and periodontal status:a prospective follow-up study.J Clin Periodontol 2006, 33 (10): 691-698., Yamamoto K, Kobayashi T, Grossi S, Ho AW, Genco RJ, Yoshie H, De Nardin E:Association of Fcgamma receptor IIa genotype with chronic periodontitis in Caucasians.JPeriodontol 2004,75 (4): 517-522., Loos BG, Leppers-Van de Straat FG, Van de Winkel JG, Van derVelden U:Fcgamma receptor polymorphisms in relation to periodontitis.J Clin Periodontol 2003,30 (7): 595-602.).(the Musolino A such as Musolino A, Naldi N, Bortesi B, Pezzuolo D, Capelletti M, Missale G, Laccabue D, Zerbini A, Camisa R, Bisagni G et al:Immunoglobulin G fragment Creceptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients withHER-2/neu-positive metastatic breast cancer.J Clin Oncol 2008, 26 (11): 1789-1796.) find that Trastuzumab can participate in the activation inactivation of Fc-gamma receptor, and then affect its relevant cytotoxicity.In conjunction with the result of prediction, can know by inference, Trastuzumab is likely by Fc gamma R-mediated phagocytosis this process influence systemic loupus erythematosus and periodontitis.

Other 5 kinds of medicines (Bevacizumab, Adalimumab, Rituximab, Quetiapine, Olanzapine, Trastuzumab) are predicted the outcome as following table 4-table 8, below in form & represent that the medicine of FDA approval cures mainly function; * for there being the new curative effect of medicine of bibliographical information.

The Bevacizumab associated disease forecasting (TOP 10) of table 4. based on bioprocess spectrum

The Adalimumab associated disease forecasting (TOP 10) of table 5. based on bioprocess spectrum

@Mena Soory.Association of periodontitis with rheumatoid arthritis and atherosclerosis：Novelparadigms in etiopathogeneses and management？Open Access Rheumatology：Research andReviews 2010：21-16.

The Rituximab associated disease forecasting (TOP 10) of table 6. based on bioprocess spectrum

The Quetiapine associated disease forecasting (TOP 10) of table 7. based on bioprocess spectrum

@United States Patent 7338948 Use of quetiapine

The Olanzapine associated disease forecasting (TOP 10) of table 8. based on bioprocess spectrum

To sum up, method design based on the new curative effect of bioprocess prediction medicine of the present invention is ingenious, can comparatively comprehensively assess the relation of medicine-disease, for finding the new medicine of disease, the potential toxic and side effect of medicine is found, expand the treatment functional space of existing medicine and " old " medicine newly with etc. have great significance, be suitable for large-scale promotion application.

In this instructions, the present invention is described with reference to its specific embodiment.But, still can make various amendments and conversion obviously and not deviate from the spirit and scope of the present invention.Therefore, instructions and accompanying drawing are regarded in an illustrative, rather than a restrictive.

Claims (6)

1. the method based on the new curative effect of bioprocess prediction medicine, is characterized in that, comprises the following steps:

(1) build disease bioprocess spectrum and medicine bioprocess spectrum;

(2) in bioprocess spectrum aspect, calculate the relevance score of medicine-disease;

(3) conspicuousness of measurement relevance score;

(4) screening has the medicine-disease relationship of conspicuousness, and user can, according to relevance score ranking results, carry out further experimental demonstration to the function of medicine;

Wherein, described step (2) specifically comprises the following steps:

(21) choose the bioprocess of medicine, the equal appreciable impact of disease, in bioprocess spectrum aspect, calculate the relevance score of medicine-disease;

In described step (21), adopt the product of the influence degree of medicine to bioprocess and the influence degree of disease to bioprocess to add and calculate the relevance score of medicine-disease, see following formula (I):

Wherein S _{drug, disease i}: the relevance score of medicine-disease i; p _{drug, k}: the p value of the enrichment of medicine on bioprocess k; p _{disease i,k}: the p value of the enrichment of disease i on bioprocess k; K: disease i and medicine be the bioprocess of appreciable impact all.

2. the method based on the new curative effect of bioprocess prediction medicine according to claim 1, is characterized in that, described step (1) specifically comprises the following steps:

(11) build bioprocess data set;

(12) build disease and disease related protein data set;

(13) the target spot data based on medicine and bioprocess data set, calculates the influence degree of medicine to bioprocess, obtains the bioprocess spectrum of medicine; Based on disease and disease related protein data set and bioprocess data set, calculate the influence degree of disease to bioprocess, obtain disease bioprocess spectrum.

3. the method based on the new curative effect of bioprocess prediction medicine according to claim 2, it is characterized in that, in described step (13), adopt Fisher ' s exact test to calculate influence degree and the disease influence degree to bioprocess of medicine to bioprocess.

4. the method based on the new curative effect of bioprocess prediction medicine according to claim 1, is characterized in that, described step (3) specifically comprises the following steps:

(31) build the random bioprocess spectrum of medicine;

(32) distribution situation of the relevance score of the random bioprocess spectrum of calculating medicine and disease, whether the relevance score of statistical test medicine-disease is significantly higher than stochastic distribution.

5. the method based on the new curative effect of bioprocess prediction medicine according to claim 4, is characterized in that, in described step (32), whether the relevance score of weighing medicine-disease by calculating Z-score has conspicuousness:

Wherein S _{drug, disease i}: the relevance score of medicine-disease i; Average (S _{random, disease i}): the relevance average of the random bioprocess spectrum of medicine and disease i; Std (S _{random, disease i}): the relevance standard deviation of the random bioprocess spectrum of medicine and disease i.

6. the application of the method based on the new curative effect of bioprocess prediction medicine according to claim 1 in the new curative effect of prediction medicine.