基于结构的药物分子设计ppt课件

1、基于构造的药物分子设计一、概略二、药物设计的实际根底三、知受体构造的药物设计四、未知受体构造的药物设计五、药物设计与组合化学的关系六、展望药物研发的平均周期 先导化合物及其优化随机挑选1000020000个化合物药物候选物临床前研讨临床研讨市场实际计算、分子模拟计算机辅助药物设计23年23年23年23年34年平均1012年，耗资2.0亿3.5亿美圆处理问题的出路是尽快提高我国药物设计的程度我国制药工业的规模居于世界前列我国创制新药的才干非常有限药物开发的普经过程先导化合物的产生先导化合物的优化活性测定临床前研讨临床研讨药物 10-12 年的时间药物设计的分类1、知受体三维构造的情形根据受体构造

2、寻觅新类型的先导化合物受体与知化合物作用研讨，先导物的优化复合物晶体构造探针搜索法自在能微扰计算2、未知受体三维构造的情形系列化合物的定量构效关系研讨药效团模型基于构造的药物分子设计一、概略二、药物设计的实际根底三、知受体构造的药物设计四、未知受体构造的药物设计五、药物设计与组合化学的关系六、展望药物设计的实际根底 药物与受体作用的锁-钥模型 刚性作用，诱导契合 实验方法：X-射线晶体学，NMR，CD，荧光，微量量热法，等 基于药物作用机制的设计 刚刚开场Two Key Issues in Lock-Key Model How to dock the drug molecule to its

3、targetdifferent docking algorithms rigid docking: rotation & translation soft docking How to calculate the binding free energyProblems in Molecular Recognition attractions when they are far away conformational changes and induced fit energetic terms desolvation dipole-dipole, orbital.分子识别与分子对接 分

4、子识别的作用根底-分子间弱相互作用 van der Waals interaction H-bonds electrostatic dipole-dipole orbital-orbital solvent effect . 分子识别的广泛存在性 生物大分子的相互作用，信号传导，生物调控 资料组装 超分子 催化剂设计.分子对接计算一、刚体对接旋转+平移， 6个自在度1. 知作用位点及一组间隔限制 间隔几何算法 Monte-Carlo 模拟退火 对接初始位置确定三个随机数：1哪个自在度变2变化步长平移2埃，旋转45度3能否接受变化Edock = K(ri)(ri - r0)2K(ri) = 50

5、0 ri1.5埃CAB6rr2. 未知作用位点外形互补外表方式互补外表最小二乘拟合computer-vision mehtod3. 打分规范几何匹配好坏结合能结合面分析对于蛋白质-蛋白质如抗原-抗体，酶-蛋白抑制剂interface area 1500埃2，hydrogen bonds: 813 pairspacking density: similar to protein core二、柔性对接1. Soft docking 外表平滑处置，允许原子相互穿透2. 配体构象变化 受体-多肽体系，受体诱导多肽构象变化3. 受体构象变化 侧链构象， 主链4. 受体+配体构象变化 induced-fi

6、t常用的对接程序DOCK4.0AutoDockFlexFT-DOCKGRAMM.References for Docking1. Curr. Opin. Struc. Biol. 1993, 3:265-2692. Protein Engineering 1994, 7:39-46Molecular surface recognition by a computer vision-based technique3. J. Mol. Biol. 1992, 225:849-858Docking by least-squares fitting of molecular surface patte

7、rnsSCORE: A New Empirical Method for Estimating the Binding Affinityof a Protein-Ligand ComplexRenxiao Wang, Liang Liu, Luhua Lai, and Youqi TangInstitute of Physical Chemistry, Peking UniversityJ.Mol.Model. 1998, 4, 379-394.Why to predict binding affinity?Database searchDe novo methodManually desig

8、nRank the candidatesSynthesis&bioassayIt is the central issue in structure-based drug design.Energetics of the Binding Process Dissecting the binding free energy into componentsFInteraction energy between ligand and protein(enthalpic)FOverall loss in entropy due to association(entropic)FHydropho

9、bic effect(entropic)FEntropy loss due to rotational constraints(entropic)FChanges in conformational energy upon binding (enthalpic)=+Protein-Ligand InteractionsElectrostatic interactionCoordinate bonding with metal ionVan der Waals interactionHydrogen bondingKinteraction = k1KSB + k2KIB+ k3KVC + k4K

10、VB + k5KHBSCORE equation.constmetalRotorcHydrophobibondHVDWdKKKKKpK Taking account for VDW interaction, hydrogen bonding, hydrophobic interaction, deformation entropy loss and metal-bonding upon protein-ligand binding process.Correlation between the calculated pKd values andthe experimental values o

11、f 170 protein-ligand complexesAtomic Binding ScoreThe overall binding affinity can be decomposedinto the contribution of individual atoms.ALOHA!XLOGP: A New Atom-Addition Method for Calculating Partition CoefficientsRenxiao Wang, Ying Fu, and Luhua LaiInstitute of Physical Chemistry, Peking Universi

12、tyJ.Chem.Infput.Sci. 1997, 37, 615-621Using 80 atom types (C, H, O, N, S, P, halogens)and 5 correction factorsijjjiibmanPlogCorrelation between the calculated logP values and the experimental values of 1831 organic compoundsMolecular lipophilicity potential (MLP)of melatonin文献阅读及讨论要求Murray, C.W., Baxter, C.A., Frenkel, A.D., The sensitivity of the results of molecular docking to induced fit effects: Application to thrombin, thermolysin and neuraminidase. J. Compt.-Aide