1、Virtual Screening for Anti-tumor Drug Discovery虛擬篩選在抗腫瘤藥物研發中的應用Master of Small Molecules您身邊的抑制劑大師內容提要 HTS for Anti-tumor Chemicals 抗腫瘤藥物的高通量篩選 VS for Anti-tumorchemicals 虛擬篩選的應用 ToolsforVS 虛擬篩選小工具Cancer 癌癥人類健康殺手Cancer is one of humanitys greatest health challenges.Cancer is the first or second leadi

2、ng cause of death before the age of 70 years in 112 of 183countries and ranks third or fourth in a further 23 countries in 2019.Global cancer statistics 2020. /10.3322/caac.216603MCE Master of Small MoleculesChemicals in cancer treatment 抗腫瘤藥物Chemotherapy and molecularly targeted therapy remain the

3、mainstay for the treatment of cancer Chemotherapy Alkylating agents: Ifosfamide, Arenobufagin, Etoposide Antimetabolite agents: 5-Fluorouracil, 6-Mercaptopurine, Carmofur Targeted therapy Ribociclib/Palbociclib/Abemaciclib:CDK, Cell Cycle/DNA Damage Tivozanib:VEGFR, Protein Tyrosine Kinase/RTK Venet

4、oclax:Bcl-2, Apoptosis/Autophagy Imatinib:BCR/ABL, v-Abl, PDGFR, tyrosine kinases Epacadostat: IDO1 Nolatrexed: TS, Cell CycleMolecules. 2020 Dec 7;25(23):5776.4MCE Master of Small MoleculesScreening Strategies 篩選策略 Target-Based Screening 基于已知靶點，篩選出的化合物機理清楚 篩選范圍明確，得到候選化合物的概率更高 Phenotypic-Based Scree

5、ning 靶點未知，篩出的化合物的作用機理不清楚 篩選范圍寬泛，需要用大量的化合物進行篩選Bioorg Med Chem. 2012 Mar 15;20(6):1922-8.5MCE Master of Small MoleculesDrug Development Process 藥物研發流程Time-consuming （13-15）High-cost($2.6billion)LowSuccessRate(1/50001/10000)Nat Rev Drug Discov. 2008 Jul;7(7):591-6076MCE Master of Small MoleculesHTS Cas

6、e Study - Discovery of Epacadostat 依帕司他研發過程EpacadostatDiscovery ofIDO1 inhibitors（IncyteCorporation）Lead optimization Preclinical studys.clinical studys. high throughput screenof300000 compounds; Test absorbance of N- formlylkynurenine in 321nm. Get one lead compound with high potency and selectivit

7、y to IDO1, but with poor oralbioavailability. Synthesization of series ofderivatives(2000compounds). Improve the permeability and oral bioavailability. In vitro & in vivo Biological Assays Pharmacokinetic Assayscombination withantiPD1 mAb,pembrolizumab for thetreatment of patientswith melanoma . Mol

8、ecularmodelling Enzyme KineticsACS Med. Chem. Lett. 2017, 8, 486-4917MCE Master of Small MoleculesVirtual Screening: Faster, Cheaper虛擬篩選in silico structure-based drug design - SHIFTING THE BOTTLENECK? Drug Discovery World Spring 20038MCE Master of Small Molecules內容提要 HTS for Anti-tumor Chemicals 抗腫瘤

9、藥物的高通量篩選 VS for Anti-tumorchemicals 虛擬篩選的應用 ToolsforVS 虛擬篩選小工具Types of VirtualScreening虛擬篩選類型Ligand-Based Virtual Screening (LBVS)Compound CompoundTarget Compound Structure-Based Virtual Screening (SBVS)10MCE Master of Small MoleculesLigand-Based Virtual Screening 基于藥效團的虛擬篩選 對特定靶點中相同結合位點有活性的配體集合 指定藥

10、效團特征，疊合配體構象獲得藥效團模型 驗證藥效團模型有效性 虛擬篩選Training set 根據打分值、結構多樣性等，挑選化合物構建藥效團驗證Pharmacophore Model篩選打分、排名 生物測試100K Compounds1000 CompoundsDiscovery Studio11MCE Master of Small MoleculesPharmacophore Model藥效團模型Discovery Studio12MCE Master of Small MoleculesCase Study: Nolatrexed諾拉曲塞 Name of the drug:Nolatre

11、xed Disease indication: Unresectable hepatocellular carcinoma (HCC). Target:Thymidylate Synthase (TS) enzyme. Clinical trial status:Phase III clinical trial completed.Understanding the Basics of Qsar for Applications in Pharmaceutical Sciences & Risk Assessment, 2015:427-453.13MCE Master of Small Mo

12、leculesQSAR of Nolatrexed 諾拉曲塞藥物結構與活性酮喹唑啉環Electron density map ofcompound 8 complexedwith E. coli TS and 5-FdUMF Representation of E. coli TS containing bound FdUMP andCB3717 (PDDF).J. Mol. Biol. (1990) 214, 9233936J. Med. Chem. 1993,36, 733-74614MCE Master of Small MoleculesMolecular Docking & Stru

13、cture-Based Virtual Screening分子對接&基于受體的虛擬篩選 What is Docking ？ What is Structure-Based Virtual Screening？Nat Rev Drug Discov. 2004 Nov;3(11):935-49.15MCE Master of Small MoleculesStructure-Based Virtual Screening 基于受體結構的虛擬篩選Binding Site Determination Grid Construction3D Structure OptimizationConforma

14、tion GenerationNature. 2004 December 16; 432(7019): 862865.16MCE Master of Small MoleculesCaseStudy: 2019-nCoV 3CLpro (Mpro) 靶向 Mpro 的小分子化合物虛擬篩選3C 蛋白酶 (3C protease, 3Cpro) 是催化 RNA 病毒前體蛋白中非結構蛋白裂解的關鍵蛋白酶，對病毒的復制有著重要作用，是當前抗病毒研究的一個重要靶點。而負責冠狀病毒復制的關鍵酶主蛋白酶 (Main Protease, Mpro) 具有與小 RNA 病毒3C 蛋白酶相似的切割位點特異性，因此

15、也稱為 3C 樣蛋白酶/3CL 水解酶 (3C like Protease,3CLpro上科大饒子和/楊海濤團隊PDB ID: 6LU7Structure of Mpro from COVID-19 virus and discovery of its inhibitors.17MCE Master of Small MoleculesBinding Site Determination of 2019-nCoV3CLpro 結合位點確認90oPDB ID: 6LU718MCE Master of Small MoleculesGrid Construction of 2019-nCoV3CL

16、pro格點文件構建格點文件的構建 對接驗證19MCE Master of Small MoleculesVirtual Screening of 2019-nCoV3CLpro 虛擬篩選180o+ =HY-L035PPDB ID: 6LU720MCE Master of Small MoleculesVirtual ScreeningProject虛擬篩選報告Top 200 CompoundsSchrdinger 2D/3D Cartoon RepresentationPyMol21MCE Master of Small MoleculesVirtual Screening Project 虛

17、擬篩選報告Binding Pocket of 2019-nCoV 3CLpro22MCE Master of Small MoleculesVirtualscreening and leadoptimization 虛擬篩選和先導物優化Curr Top Med Chem. 2010;10(1):127-41.23MCE Master of Small Molecules內容提要 HTS for Anti-tumor Chemicals 抗腫瘤藥物的高通量篩選 VS for Anti-tumorchemicals 虛擬篩選的應用 ToolsforVS 虛擬篩選小工具Compound Librar

18、y 小分子化合物庫化合物庫作為虛擬篩選的重要工具，決定了小分子藥物研發的速度和質量。千億數百億按需定制化合物增長需求量 (NPMI分析)25MCE Master of Small MoleculesZINC20ZINC( HYPERLINK / )化合物信息的公開數據庫，支持2D、3D化合物分子形式下載、快速分子查找、類似物搜索，分子數量近20億。新增10億個按需定制化合物。26MCE Master of Small MoleculesMCE Library 90+ 生物活性化合物庫； 13300+活性確認化合物可 14000+片段化合物； 結構多樣；供篩選； 涵蓋500+生物靶點及多種 高溶

19、解度（90%以上可以達到 200mM以上溶解度） 高純度；熱門研究領域； 支持高度定制。 1600萬化合物可供篩選 結構多樣性 高類藥性 庫存充足，可重復供應27MCE Master of Small MoleculesScreening Compound Databases (Part)2,800K，有庫存270K，有庫存500K，有庫存2,244K，有庫存200K，有庫存1,300K，有庫存1,000K，有庫存680K，有庫存1,400K，有庫存 485K，有庫存1,400K，有庫存 1,300K，有庫存28MCE Master of Small MoleculesCommon Libra

20、ries/virtual-screening.htmlCat. No. Product Name Format/SizeHY-L001V MCE Bioactive Compound Library 12,781HY-L0053V Premium Library 43,525HY-L0055V Discovery Diversity Set 50 50,240HY-L0088V Life Chemicals 50K Diversity Library 50,240HY-L0086V Specs HTS Compounds Library 210,070HY-L0056V Hit Locator

21、 Library 234,115HY-L0052V Advanced Library 482,182HY-L0087V Life Chemicals HTS Compound Collection 465,800HY-L0051V HTS Compound Library 2,121,382HY-L0094V Chinese National Compound Library 1,400,00029MCE Master of Small MoleculesHot Targeted LibrariesCat. No. Product Name Format/Size DescriptionHY-

22、L0058V GPCR Library 54,080 Designed for discovery of new GPCR ligands.HY-L0061V Kinase Library 64,000 Designed for discovery of novel protein kinase inhibitors.HY-L0064V Ion Channel Library 36,800 Designed for discovery of new Ion Channels ligands.HY-L0065V CNS Library 38,080 Library of novel small

23、molecules with high CNS MPO scores.HY-L0066V Protein-Protein Interaction Library 40,640 Designed for discovery of novel PPI inhibitors.HY-L0067V Immuno-Oncology Library 52,935Designed for discovery of novel hits in Immuno-Oncologytherapeutic area.HY-L0073V Antiviral Library 3,700 Nucleoside-like com

24、pounds able to act as antiviral.HY-L0076V Covalent Screening Library 14,249A set of screening compounds bearing “warheads” for covalenttarget modification.30MCE Master of Small MoleculesProtein Structure 蛋白結構天然蛋白質具有特定的三維空間立體結構。一生二，二生三，三生空間結構，構成蛋白質肽鏈的氨基酸線性序列 (一級結構) 包含了形成復雜三維結構所需要的全部信息。31MCE Master of

25、 Small Molecules現有蛋白三維結構少18萬個實驗測定的蛋白質三維結構/0.8621,000萬個蛋白質已知氨基酸序列/32MCE Master of Small Molecules實驗測定三法寶X-ray，NMR，冷凍電鏡高質量蛋白單晶，精度高小蛋白，無精度大蛋白，精度低，3以上33MCE Master of Small Molecules預測蛋白三維結構限制多34MCE Master of Small MoleculesAlphaFold2，從精度到廣度 2020年末，AlphaFold2在CASP14中將蛋白結構預測準確性從40 分拔高到92.4分，實現了原子精度或者接近原子精

26、度的結構預測； 2021年7月16日，DeepMind團隊在Nature上公布了AlphaFold2的源代碼； 2021年7月22日，DeepMind團隊再發Nature，公布AlphaFold數據集https:/alphafold.ebi.ac.uk； AlphaFold數據集覆蓋幾乎整個人類蛋白質組（的所有人類 蛋白），還包括大腸桿菌、果蠅、小鼠等20個科研常用生物的蛋白 質組數據，蛋白質結構總數超過個！而且，數據集中的預 測結構達到可信水平，其中更有35.7%達到高信度。35MCE Master of Small Molecules36MCE Master of Small Moleculestibody-dr