<p>&lt;p&gt;Chapter 2 Drug screening &amp;amp; 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 granisetronpalonosetron Ondansetron 血管紧张素转化酶（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-Arg Angiotensin I Bradykinin: 血管舒张剂 ACE Arg-Pro-Pro-Gly-Phe-Ser-Pro Hypothetical active site of carboxypeptidase A Hypothetical binding of inhibitors to ACE captoprilenalaprilEnalaprilat (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 H2受体拮抗剂类抗溃疡药 ? 选定靶点组胺H2受体 (确立研发目标抑制胃酸分泌药物) ? 建立动物筛选模型麻醉兔灌胃 ?从H2受体天然激动剂组胺入手，以其为先导结构，保留咪唑环，改变侧链，开 始优化 IIb/IIIa糖蛋白受体拮抗剂 ?血栓形成的关键步骤是纤维蛋白原与血小板IIb/IIIa受体结合。 ?被IIb/IIIa受体识别和相互作用的主要区段是纤维蛋白原的三肽片断Arg-Gly- Asp（RGD）。 ?蛇毒或水蛭素中含有RGD的线形或环状肽，是阻断IIb/IIIa受体活化从而抑制血 小板聚集的药效团。 ?含有或模拟RGD结构的肽或拟肽可作为纤维蛋白原的拮抗剂，是创制抗血栓 药物的一个新途径。 RGD Sibrofiban Roxifiban 4、SOSA 磺胺治疗细菌感染时，发现利尿作用. Acetazolamide 口服利尿 Dichlorphenamide chlorthiazide hydrochlorthiazide cyclothiazide 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 sulfasomizole Carbutamide, 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 iproniazid phenelzine tranylcypromineselegiline 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 sildenafil cGMP?NO?第二信使 增强勃起功能(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) cisplatincarboplatin oxaliplatinlobaplatin More good luck: Target Library Synthesis Full screening Lipinskis RO5 Fragment grow, link and merge Fragments: Fragment-based Screening High Throughput Screening 102 104 RO3 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 discovery Fragment Library Target X-ray / NMR Structures b c a NMR Competitive Binding Experiment Evolution Validation Biacore HSQC *Hubbard et al (2007), Curr Topics Med Chem, 7, 1568 Biacore Fragment Based Lead Discovery Clinical candidates of fragment-derived compounds CompoundCompanyStatusTargetTherapy areas VemurafenibPlexxikon/R oche Phase IVB-RAFMelonoma (first FBDD drug on market, FDA approved in 2011) ABT-263Abbott Genentech Phase IIBcl-xLSmall-cell lung cancer, CML, Lymphoma, Hematological neoplasm Cancer ABT-869AbbottPhase IIVEGF and PDGF receptor tyrosine kinase family members Non-small-cell lung cancer, etc. AT-7519AstexPhase IICDK family members Multiple myeloma cancer AT-9283AstexPhase IIAurora kinase family members Flt3 tyrosine kinase, Jak2 tyrosine kinase Abl tyrosine kinase Hematological neoplasm Solid tumor CompoundCompanyStatusTargetTherapy areas DG-051deCODEPhase IILeukotriene A4 hydrolase Myocardial infarction PLX-204PlexxikonPhase IIPPAR alpha, delta, gamma Inflammatory disease Cardiovascular disease Non-insulin dependent diabetes LY-517717Lilly TularikPhase IIFactor XaThrombosis NVP-AUY- 922 Vernalis Novartis Phase IIATPase Hsp 90Cancer Solid tumor ABT-518AbbottPhase IGelatinase Metalloprotease-2 Metalloprotease-9 Solid tumor IC-776Lilly ICOSPhase ICD11a, ICAMInflammatory disease, Psoriasis, Autoimmune disease AT-13387AstexPhase IHsp 90Cancer CompoundCompanyStatusTargetTherapy areas PLX-4032Plexxikon Roche Phase IRaf B protein kinase Melanoma Cancer PLX-5568Plexxikon Roche Phase IRaf protein kinasePain, Polycystic kidney disease SNS-314SunesisPhase IAurora protein kinase Cancer solid tumor AT-13148Astex, ICR CRT AstraZeneca Phase IAKT protein kinase Cancer SGX-393Lilly (SGX)IND for Phase I Abl tyrosine kinase Cancer Ref: Expert Opin. Drug Discov. (2009) 4:1125 Weak binding between the target and a small molecule fragment is detected by biophysical methods, e.g., NMR, SPR or cross-validated by these two techniques. Fragment Selection RO3: 110 &amp;lt; MW &amp;lt;250 300 cLogP &amp;lt; 2 3 (or cLogD &amp;lt; 2 3) 2 &amp;lt; N+O -4.5 TPSA 10mg? Low hit rate, low throughput ? Heavily involved in H2L, LO. NMR1KY&amp;gt;10mg? High hit rate (28%, indicate druggability). ? Ligand based (STD &amp;amp; WaterLOGSY) observation in cocktail ?Less false positive results ITC1 2K Ng SPR2 5KYmg? 3 weeks screening ? Cross validation with NMR HCS5 30KY? require bioassay development for different targets (difficulty in outsourcing) ? High false positive rate &amp;gt;10 fragment derived compounds in clinical phase II from pharmaceutical companies, e.g., Novartis, Lily, Abbott, Genentech, Astex, Vernalis, deCODE, Plexxikon. &amp;gt;20 fragment derived compounds in clinical phase I since 2005. Hits to leads Evolving Fragments - In Practice Known Ligands Detailed Design NVP&lt;/p&gt;</p>