第15讲-计算机辅助药物设计(1).ppt

A 3D model of SARS_CoV 3CL proteinaseand its inhibitors design by virtual screening severe acute respiratory syndrome(SARS) Genomic sequencing and bioinformatics analyses have addressed the important proteins that may be associated with the SARS coronaviruse (SARS_CoV) infection, including the polymerase, the spike (S) glycoprotein, the envelope (E) Protein, the membrane (M) protein, the nucleocapsid (N) protein, and the 3C-like (3CL) proteinase Target---SARS_CoV 3CL proteinase Get the sequence: GenBank protein ID P_828863 (/ ) Search the homologous protein: BLAST---43 BLAST hits (PDB: /pdb/) the template----the main proteinase (Mpro) of transmissible gastroenteritis virus (TGEV), the sequence identity is 43 %, positive 60 %, and gap 1 %. Model the SARS_CoV 3CL proteinase Binding site mapping Module: SiteID, MOLCAD Result: the atomic RMSD between the two pockets is only 0.18 ?, indicating the spatial structure and shape of the substrate binding pocket of the SARS_CoV 3CL protease is similar to that of the TGEV Mpro. Virtual screening several databases: MDL: ACD, MDDR SPECS the China Natural Product Database (CNPD) compound sample database of the National Center for Drug Screening performed on the 64-processor SGI Origin 3800 supercomputer at the Drug Discovery and Design Center and the 392-processor Sunway-1 supercomputer at the Shanghai Supercomputer Center DOCK4.0--------top 1000 compounds Radius : 6 ? protein Charges: Kollman-all-atom the small molecules’ charges:Geisterger-Hückel CScore + AutoDOCK3.0------100 compounds 抗流感病毒药物 神经氨酸酶 实验发现2-去氧-2,3-双去氢-D-N-乙酰神经氨酸（Neu5Ac2en）对神经氨酸酶（又称唾液酸酶）有抑制作用，但在动物模型中效果不佳。 通过实验测定了唾液酸酶的晶体结构 及酶与抑制剂Neu5Ac2en的晶体结构 基于唾液酸酶结构的药物设计 唾液酸酶晶体结构 GRID扫描晶体结构：有亲正电荷作用位点 引入基团后计算: 4-氨基-Neu5Ac2en; 4-胍基-Neu5Ac2en 抑制活性测定表明4-氨基和4-胍基取代Neu5Ac2en，比其母体Neu5Ac2en分别提高20倍和5000倍，后者为Zanamivir。 Zanamivir 生物信息技术为药物研究设计提供了崭新的研究思路和手段，已经在新药设计的各个环节，如初始阶段、筛选及药物设计，以及新药开发阶段发挥着越来越重要的作用。利用强大的计算工具，新药开发平均费用降为8亿美元，时间则缩短了2