从基于结构到基于系统的药物设计

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1、从基于结构到基于系统的药物设计从基于结构到基于系统的药物设计北京大学化学与分子工程学院，物理化学研究所 分子动态与稳态结构国家重点实验室 北京大学理论生物学中心北京大学化学与分子工程学院，物理化学研究所 分子动态与稳态结构国家重点实验室 北京大学理论生物学中心Protein-protein interaction and protein designProtein-protein interaction and protein designBinding affinity calculation： Jiang L, Lai LH, et al., Proteins 2002; J Biol C

2、hem 2002; Liu SY, Li QL, Lai LH, Proteins 2006 Protein-protein interface analysis： Gao Y, Wang RX, Lai LH, J Mol Mod 2004 Conformational flexibility and function： Ma WZ, Tang C, Lai LH, Biophys J 2005; Proteins, in pressFunctional site grafting method：Liang SD, Lai LH, et al., Biopolymer 2000Protein

3、 side chain packing：Liu ZJ, Lai LH, et al., Proteins 2003Functional protein design targeting protein interface：Liu S, Liu SY, Cao AN, Chang ZJ, Lai LH, et al., PNAS 2007Registered Users (before 9/1/06)1676167698988585530530340340410410总 用 户总 用 户合计合计PLOG PPLOG PPP_ SIT EPP_ SIT ELIGBUI LDERLIGBUI LDE

4、RSCOR ESCOR EXLOGPXLOGPFrom Structure Based to Systems Based Drug DesignFrom Structure Based to Systems Based Drug DesignSTRUCTURE BASED DRUG DESIGNYang K, Ma WZ, Ouang Q, Tang C, Lai LH, et al., PLoS Compt. Biol. 2007Programs developed can be downloaded at： http:/JCIM 1997,1998;JMM 2000, 2001; Pers

5、pective Drug Dis 2000; Proteins 2005,2006SARS 3CL proteinases: protein aggregation, enzyme reaction mechanism, and inhibitor designSARS 3CL proteinases: protein aggregation, enzyme reaction mechanism, and inhibitor designBased on the binding affinity calculation method：Jiang L, Lai LH, et al., Prote

6、ins 2002; J Biol Chem 2002Proved that only the dimer is active：Fan KQ, Wei P, Liu Y, Lai LH, et al., J Biol Chem 2004 Proposed an enzyme activity modulation mechanism through dimer formation：Chen H, Wei P, Lai LH, et al., al., J Biol Chem 2006The general base catalytic mechanism of SARS 3CL Pro：Huan

7、g CK, Liu Y, Lai LH, et al., Biochem 2004Substrate specificity and virtual inhibitor screen：Fan KQ, et al. BBRC 2005; Liu ZM, et al. JCIM 2005Specific inhibitor design and mechanism：Zhou L, Liu Y, Lai LH, et al., J. Med. Chem. 2006药物发现的一般过程先导化合物的发现 先导化合物的优化 活性测试 临床前研究 临床研究 上市药物先导化合物的发现 先导化合物的优化 活性测试

8、 临床前研究 临床研究 上市药物 10-12 年年青霉素的发现传统的药物发现方法青霉素的发现传统的药物发现方法Enzymes 28%Receptors 45%Nuclear receptors 2%DNA 2%Hormones 15(5):429-446.What is essential for a successful dock: orientation search or scoring ?Estimating Protein-Ligand Binding Free Energy: Atomic Solvation Parameters for Partition Coefficient

9、 and Solvation Free Energy Calculation-0-10-20-30-40-50-60-70-0-10-20-30-40-50-60-70Predicted binding free energy (kJ/mol)Experimental binding free energy (kJ/mol)Atomic Solvation parameter:Gs= i AiSpred = 8.31kJ/molPei JF, Lai LH, et al., Proteins 2004蛋白质与配体作用研究蛋白质与配体作用研究北 京 大 学 研 发 的 从 头 设 计 程 序北

10、京 大 学 研 发 的 从 头 设 计 程 序COMPUTER BASED DE NOVO DESIGN OF DRUG LIKE MOLECULES G Schneider and U Fechner, Nature Rev. Drug Dis., 2005,4, 649LigBuilder: A software package for de novo ligand building-upPOCKETLINKGROWPharmacophoreTarget ProteinLigandsWang RX, Lai LH, et al., J. Mol. Mod. 2000药物从头设计药物从头设计

11、?Based on the previously developed LigBuilder program,?Compound synthesis accessibility was introduced, plus to druglikeness, toxicity analysis. New developments on de novo drug design method苑亚夏、裴剑锋等2006年9月1日以前注册的用户1676167679985485805303404107998548580530340410总 用 户合计总 用 户合计PSI- DOCKPLOGPFLARMPP_SIT

12、EAOS/APSLIGBUILDERSCOREXLOGPPSI- DOCKPLOGPFLARMPP_SITEAOS/APSLIGBUILDERSCOREXLOGP具有自主知识产权的药物设计程序具有自主知识产权的药物设计程序 http:/http:/蛋白质与配体作用研究蛋白质与配体作用研究基于结构的药物设计小结基于结构的药物设计小结 基于药物与靶标的相互作用。 可以根据靶标的三维结构，利用匙钥模型进行有 针对性的药物设计。主要方法有数据库搜索，片 段组装，从头设计。 药物与靶标结合自由能的精确计算是难点之一。 结合过程中分子的构象变化是另一难点。 未知靶标结构时，从已知的活性化合物出发进行 三维

13、定量构效关系研究。Nature Biotechnology 22, 1253 - 1259 (2004), Systems biology in drug discovery Eugene C Butcher1, 2, Ellen L Berg3 Networked systems might require multicomponent interventions to modulate signalling outputs.如何有效地控制疾病相关的分子网络Many diseases are related to inflammatory disorders Alzheimers disea

14、se Asthma Multiple sclerosis Osteoarthritis Rheumatoid arthritis Type I diabetes mellitus and more What causes inflammation inflammatory mediatorsProstaglandins (PGs)Leukotrienes (LTs)12 enzymes, 19 compounds, 24 forward pathways, 24 feedback (positve 6, negative 18)ODE equations 24 equations 45 par

15、ameters, 23 were fitted 24 initial conditions 2)1521 (22211919PGHKHETE KAA KPGEkPGHPGESk dtPGEdiii+=)2*15*(54TXASPGHKHPETEKdtTXASd ii+=Fig.1 The normal flux analysisFig.2 The flux analysis when inhibit COX-2Fig.3 The flux analysis when inhibit 5-LOXFlux changes when inhibitors are addedK Yang, WZ Ma

16、, HH Liang, C Tang, Q Ouyang, LH Lai, PLoS Compt. Biol. 2007Onefold inhibitors of 5-LOX or COX-2 are not enough to control inflammationWhen the total amount of LTs are reduced to 10-20%, the production of PGE2 increases by 73%-88%.K Yang, WZ Ma, HH Liang, C Tang, Q Ouyang, LH Lai, PLoS Compt. Biol. 2007Nonsteroidal