chapter2drugscreeningdiscovery(design)-在線瀏覽
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【正文】 OO HO HO脂 肪 酶酰 化糖 苷 化糖 苷 酶氧 化鹵 過(guò) 氧 化 酶氯 代首 輪 衍 生 物 2 0 個(gè)酰 化 ：酯 ， 酰 胺碳 酸 酯氨 甲 酸 酯糖 苷 化 ：糖 苷氨 基 糖 苷糖 酸 苷氧 化 還 原 ：羥 基 化氧 化脫 甲 基 化鹵 化 ：氯 代溴 代碘 代第 二 輪 衍 生 物 共 6 0 0 個(gè)巖 白 菜 內(nèi) 酯OOO HH OC H3OO C O R1O C O R2O C O R3OImpact of highthroughput screening in biomedical research Macarron, R. NATURE REVIEWS DRUG DISCOVERY 10: 188195 (2020) 基于配體或底物的分子設(shè)計(jì) ? 酶反應(yīng)過(guò)程：酶抑制劑 – 酶結(jié)構(gòu) – 底物、過(guò)渡態(tài)、產(chǎn)物結(jié)構(gòu) – ACEI、 COX GABAT、 MAO抑制劑等 ? 抗代謝物：酶抑制劑，致死合成 ? 與受體作用過(guò)程：激動(dòng)劑或拮抗劑 – 受體結(jié)構(gòu) – 配體結(jié)構(gòu) – 腎上腺素能藥物、膽堿能藥物、甾體藥物等 5hydroxytryptamine (5HT)：神經(jīng)遞質(zhì)，低水平 〉 偏頭痛 5HT receptor isomers: 5HT1, 5HT2, 5HT3 N HN H 2O HNHN H 2ON H 2ON HNHN H 2CH 3SON HNHN H 2CH 3OSON HNHNCH 3OC H 3C H 3Activity(5HT1) = 2 (vs. 5HT) Activity(5HT2) = 1/25 Sumatriptan （ GSK， 2020 expired)：Activity(5HT1) = 188。 5HT3 止吐，胃動(dòng)力藥 Clebopride Dopamine blocker 胃動(dòng)力不變 5HT3 blocker clebopride 300 folds 無(wú) dopamine 拮抗 Setrons: 治療腫瘤化療引起的惡心嘔吐 granisetron palonosetron Ondansetron 血管緊張素轉(zhuǎn)化酶（ angiotensinconverting enzyme, ACE)抑制劑 AspArgValTyrIleHisProPheHisLeu AspArgValTyrIleHisProPhe ACE （ angiotensin II: 強(qiáng)效收縮血管） ArgProProGlyPheSerProPheArg Angiotensin I Bradykinin: 血管舒張劑 ACE ArgProProGlyPheSerPro Hypothetical active site of carboxypeptidase A N H C HRCON H C H CC H2OOZ n+ +S1S139。N C HOCC HN HR2OOCCOC HR3N HHS239。 ? 被 IIb/IIIa受體識(shí)別和相互作用的主要區(qū)段是纖維蛋白原的三肽片斷 ArgGlyAsp（ RGD）。 ? 含有或模擬 RGD結(jié)構(gòu)的肽或擬肽可作為纖維蛋白原的拮抗劑，是創(chuàng)制抗血栓藥物的一個(gè)新途徑。s RO5 Fragment grow, link and merge Fragments: Fragmentbased Screening High Throughput Screening 102 ~104 RO3 pounds (~106 pounds, ~$$2M/Screening) Small is better (sample bigger chemical space, higher hit rate, higher Ligand Efficiency, less false positive results, more intuitive to medicinal chemists) Fragment based lead discovery Fragment Library Target Xray / NMR Structures b c a NMR Competitive Binding Experiment ON NHNOONHNNHOOHO NHNN NHNHONHNNHNNHOHONNHN NHNNNHOONH2ONHNHEvolution Validation Biacore HSQC *Hubbard et al (2020), Curr Topics Med Chem, 7, 1568 Biacore Fragment Based Lead Discovery Clinical candidates of fragmentderived pounds Compound Company Status Target Therapy areas Vemurafenib Plexxikon/Roche Phase IV BRAF Melonoma (first FBDD drug on market, FDA approved in 2020) ABT263 Abbott Genentech Phase II BclxL Smallcell lung cancer, CML, Lymphoma, Hematological neoplasm Cancer ABT869 Abbott Phase II VEGF and PDGF receptor tyrosine kinase family members Nonsmallcell lung cancer, etc. AT7519 Astex Phase II CDK family members Multiple myeloma cancer AT9283 Astex Phase II Aurora kinase family members Flt3 tyrosine kinase, Jak2 tyrosine
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