药物化学chap2a-screening课件

1、Chapter 2 Drug screening & discovery (design)口服药物的共性：Lipinski归纳的“类药5规则”(Rule of Five)，概括了类药的最低标准，即分子量在500以下；氢键的给体不超过5个；氢键的接受体不超过10个；计算的分配系数(正辛醇-水系统)clogP值不超过5。上述原则只限于化合物经被动扩散机理的吸收。化合物的柔性不宜过强。否则会存在许多种构象(RB clebopride 300 folds无dopamine 拮抗Setrons: 治疗肿瘤化疗引起的恶心呕吐granisetronpalonosetronOndansetron血管紧张素转化

2、酶（angiotensin-converting enzyme, ACE)抑制剂Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu Asp-Arg-Val-Tyr-Ile-His-Pro-Phe ACE（angiotensin II: 强效收缩血管）Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-ArgAngiotensin IBradykinin: 血管舒张剂ACEArg-Pro-Pro-Gly-Phe-Ser-ProHypothetical active site of carboxypeptidase AHypothetical binding

3、 of inhibitors to ACEcaptoprilenalaprilEnalaprilat(enalapril的代谢活性组分）ACE小分子拟肽抑制剂ACE的功能羧肽酶A的作用模式肽类抑制剂的结合模式羧烷基脯氨酸卡托普利依那普利等Crystal Structure of the Human Angiotensin-Converting Enzyme-Lisinopril Complex (2003) Nature 421: 551 4、SOSA磺胺治疗细菌感染时，发现利尿作用.Acetazolamide口服利尿Dichlorphenamidechlorthiazidehydrochlo

4、rthiazidecyclothiazide长效利尿药bendroflumethiazide长效利尿药Sulfasomizole治疗伤寒病，胰岛素释放急性和持久性低血糖sulfasomizoleCarbutamide, 更强的降糖作用，治疗糖尿病Iproniazid治疗结核病，情绪提高 抑制单胺氧化酶MAO靶标抑郁型精神病 Isoniazid无抗抑郁iproniazidphenelzinetranylcypromineselegiline抗抑郁药Zaprinast抗过敏药扩张血管、降血压抑制PDE5：治疗心绞痛cGMP：扩张血管，增加血流量sildenafilcGMPNO第二信使增强勃起功能(

5、ED)模拟创新：代谢活化活性代谢物作为先导物前药设计代谢失活软药设计5、基于代谢作用抗疟药环氯胍保泰松的代谢活化6、幸运结构解析错误PenicillinChlordiazepoxide(Roche)cisplatincarboplatinoxaliplatinlobaplatinMore good luck:TargetLibrarySynthesisFull screeningLipinskis RO5Fragment grow, link and mergeFragments:Fragment-based ScreeningHigh ThroughputScreening102 104 R

6、O3 compounds(106 compounds, $2M/Screening)Small is better (sample bigger chemical space, higher hit rate, higher Ligand Efficiency, less false positive results, more intuitive to medicinal chemists)7、Fragment based lead discoveryFragment LibraryTargetX-ray / NMR Structures bcaNMR CompetitiveBinding

7、ExperimentEvolution Validation BiacoreHSQC*Hubbard et al (2007), Curr Topics Med Chem, 7, 1568BiacoreFragment Based Lead DiscoveryClinical candidates of fragment-derived compoundsCompoundCompanyStatusTargetTherapy areasVemurafenibPlexxikon/RochePhase IVB-RAFMelonoma (first FBDD drug on market, FDA a

8、pproved in 2011)ABT-263Abbott GenentechPhase IIBcl-xLSmall-cell lung cancer, CML, Lymphoma, Hematological neoplasm CancerABT-869AbbottPhase IIVEGF and PDGF receptor tyrosine kinase family membersNon-small-cell lungcancer, etc.AT-7519AstexPhase IICDK family membersMultiple myeloma cancerAT-9283AstexP

9、hase IIAurora kinase family membersFlt3 tyrosine kinase, Jak2 tyrosine kinaseAbl tyrosine kinaseHematologicalneoplasmSolid tumorCompoundCompanyStatusTargetTherapy areasDG-051deCODEPhase IILeukotriene A4hydrolaseMyocardial infarctionPLX-204PlexxikonPhase IIPPAR alpha, delta, gammaInflammatory disease

10、Cardiovascular diseaseNon-insulin dependentdiabetesLY-517717Lilly TularikPhase IIFactor XaThrombosisNVP-AUY-922Vernalis NovartisPhase IIATPase Hsp 90Cancer Solid tumorABT-518AbbottPhase IGelatinaseMetalloprotease-2Metalloprotease-9Solid tumorIC-776Lilly ICOSPhase ICD11a, ICAMInflammatory disease, Ps

11、oriasis, Autoimmune diseaseAT-13387AstexPhase IHsp 90CancerCompoundCompanyStatusTargetTherapy areasPLX-4032Plexxikon RochePhase IRaf B protein kinaseMelanoma CancerPLX-5568Plexxikon RochePhase IRaf protein kinasePain, Polycystic kidney diseaseSNS-314SunesisPhase IAurora protein kinaseCancer solid tu

12、morAT-13148Astex, ICR CRT AstraZenecaPhase IAKT protein kinaseCancerSGX-393Lilly (SGX)IND for Phase IAbl tyrosine kinaseCancerRef: Expert Opin. Drug Discov. (2009) 4:1125Weak binding between the target and a small molecule fragment is detected by biophysical methods, e.g., NMR, SPR or cross-validate

13、d by these two techniques.Fragment SelectionRO3: 110 MW 250 300cLogP 2 3 (or cLogD 2 3)2 N+O -4.5 TPSA 10mg Low hit rate, low throughput Heavily involved in H2L, LO. NMR1KY10mg High hit rate (28%, indicate druggability). Ligand based (STD & WaterLOGSY) observation in cocktailLess false positive resu

14、ltsITC1 2K NgSPR2 5KYmg 3 weeks screening Cross validation with NMRHCS5 30KY require bioassay development for different targets (difficulty in outsourcing) High false positive rate10 fragment derived compounds in clinical phase II from pharmaceutical companies, e.g., Novartis, Lily, Abbott, Genentec

15、h, Astex, Vernalis, deCODE, Plexxikon.20 fragment derived compounds in clinical phase I since 2005.Hits to leadsEvolving Fragments - In PracticeKnown LigandsDetailed DesignNVP-AUY922Phase I/IIMergingVirtual ScreenLinkingABT-263Phase IIBAGrowingAT9283Phase IIFragment 1 mM0.07 mM0.003 mM药物化学总论（2010，p609)