chapter2drugscreeningdiscovery(design)-資料下載頁
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【導讀】Lipinski歸納的“類藥5規(guī)則”，概括了類藥的最低標準，即分。分配系數(shù)clogP值不超過5。上述原則只限于化合物經(jīng)被動擴。否則會存在許多種構(gòu)象。化合物不得含有重金屬和反應(yīng)活性基團。在受體結(jié)構(gòu)信息已知的情況下，可根據(jù)結(jié)合部位的三維結(jié)構(gòu)信息，用分子對。接方法，對互補性好、評分高的化合物，可預計有較強的親和力。體的三維結(jié)構(gòu)，可根據(jù)藥效團特征篩選虛擬庫，并以不同程度的限制條件，化合物具備自主的知識產(chǎn)權(quán)和專利保護的前景，是開發(fā)決策的重要指。所以，完備的化合物檢索查新系統(tǒng)可確?；衔锝Y(jié)構(gòu)的新穎性。docetaxel:水溶性增加，活性〉紫杉醇，–蛇毒Bungarotoxin，N2受體拮抗劑?–蛇毒Batroxobin，溶血栓酶?–蜂毒Apamin，鈣通道阻斷劑和鉀通道開放劑?同時制備含眾多分子的化合物庫
【正文】 diabetes LY517717 Lilly Tularik Phase II Factor Xa Thrombosis NVPAUY922 Vernalis Novartis Phase II ATPase Hsp 90 Cancer Solid tumor ABT518 Abbott Phase I Gelatinase Metalloprotease2 Metalloprotease9 Solid tumor IC776 Lilly ICOS Phase I CD11a, ICAM Inflammatory disease, Psoriasis, Autoimmune disease AT13387 Astex Phase I Hsp 90 Cancer Compound Company Status Target Therapy areas PLX4032 Plexxikon Roche Phase I Raf B protein kinase Melanoma Cancer PLX5568 Plexxikon Roche Phase I Raf protein kinase Pain, Polycystic kidney disease SNS314 Sunesis Phase I Aurora protein kinase Cancer solid tumor AT13148 Astex, ICR CRT AstraZeneca Phase I AKT protein kinase Cancer SGX393 Lilly (SGX) IND for Phase I Abl tyrosine kinase Cancer Ref: Expert Opin. Drug Discov. (2020) 4:1125 Weak binding between the target and a small molecule fragment is detected by biophysical methods, ., NMR, SPR or crossvalidated by these two techniques. Fragment Selection RO3: 110 MW 250 ~ 300 cLogP 2 ~ 3 (or cLogD 2 ~ 3) 2 N+O 6 logS TPSA 110 Maximize the shape and electrical diversities (Openbabel + Pipeline Pilot) to cover the chemical space for prototypical pounds High ligand efficiency LE = RTln(KD)/HAC LE improves from ~ to ~ during hits to leads (H2L) Final: 1K~2K fragment library (Commercial library: Maybridge or Chembridge) Most used Fragments Screening methods Screening method Library size Primary screening Protein amount Pros amp。 Cons Crystallography 1K N 10mg ? Low hit rate, low throughput ? Heavily involved in H2L, LO. NMR 1K Y 10mg ? High hit rate (2~8%, indicate druggability). ? Ligand based (STD amp。 WaterLOGSY) observation in cocktail ?Less false positive results ITC 1 – 2K N ~g SPR 2 – 5K Y ~mg ? 3 weeks screening ? Cross validation with NMR HCS 5 – 30K Y ? require bioassay development for different targets (difficulty in outsourcing) ? High false positive rate 10 fragment derived pounds in clinical phase II from pharmaceutical panies, ., Novartis, Lily, Abbott, Genentech, Astex, Vernalis, deCODE, Plexxikon. 20 fragment derived pounds in clinical phase I since 2020. Hits to leads Evolving Fragments In Practice NHNOHOH OONOONHOHOHNOO HOH CO 2M eOO HOHOOOHHOClO HOH M eKnown Ligands Detailed Design NVPAUY922 Phase I/II Merging Virtual Screen Linking NHOSO ONHSNONNClSOOFFFABT263 Phase II OHOFOHB A Growing NH N NHN AT9283 Phase II NH NNHNN HONHNNHNN HN HON OFragment 1 mM mM mM 藥物化學總論（ 2020， p609) “在發(fā)現(xiàn)苗頭和先導物的早期研究階段，同時關(guān)注分子的物化性質(zhì)和活性，以降低新藥研發(fā)鏈中各個環(huán)節(jié)上的風險率，已經(jīng)成為業(yè)界之共識?；谄蔚乃幬镌O(shè)計，輔以配體效率的“監(jiān)督”，已在國外許多藥廠和大學蓬勃展開，大有超過高通量篩選的勢頭。應(yīng)用 FBDD的 13年來，已有一批候選藥物進入臨床試驗階段。這種研發(fā)策略，涉及了分子藥理學、結(jié)構(gòu)生物學、分子模擬、化學合成和藥物化學等多種學科和技術(shù)，整合性很強。在我國，尚未發(fā)現(xiàn)采用該方法的研究報道。本節(jié)之目的在于呼喚和催生 FBDD在我國的實施。”
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