1、基于结构的药物分子设计一、概况二、药物设计的理论基础三、已知受体结构的药物设计四、未知受体结构的药物设计五、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筛选1000020000个化合物药物候选物临床前研究临床研究市场理论计算、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2.0亿3.5亿美元解决问题的出路是尽快提高我国药物设计的水平我国制药工业的规模居于世界前列我国创制新药的能力十分有限药物开发的一般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究临床研究药物 10-12 年的时间药物设计的理论基础 药物与受体作用的锁-钥模型
2、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 刚刚开始Two Key Issues in Lock-Key Model How to dock the drug molecule to its targetdifferent docking algorithms rigid docking: rotation & translation soft docking How to calculate the binding free energyProblems in Molecular Recognition attractions w
3、hen they are far away conformational changes and induced fit energetic terms desolvation dipole-dipole, orbital.分子识别与分子对接 分子识别的作用基础-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 材料组装 超分子 催化剂设计.分子对接计算一、刚体对接旋转+平移
4、， 6个自由度1. 已知作用位点及一组距离限制 距离几何算法 Monte-Carlo 模拟退火 对接初始位置确定三个随机数：（1）哪个自由度变（2）变化步长（平移2埃，旋转45度）（3）是否接受变化Edock = K(ri)(ri - r0)2K(ri) = 500 ri1.5埃CAB6rr2. 未知作用位点形状互补表面模式互补表面最小二乘拟合computer-vision mehtod3. 打分标准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 dens
5、ity: similar to protein core二、柔性对接1. Soft docking 表面平滑处理，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-fit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 recogni
6、tion by a computer vision-based technique3. J. Mol. Biol. 1992, 225:849-858Docking by least-squares fitting of molecular surface patternsSCORE: A New Empirical Method for Estimating the Binding Affinityof a Protein-Ligand ComplexRenxiao Wang, Liang Liu, Luhua Lai, and Youqi TangInstitute of Physical
7、 Chemistry, Peking UniversityJ.Mol.Model. 1998, 4, 379-394.Why to predict binding affinity?Database searchDe novo methodManually designRank the candidatesSynthesis&bioassayIt is the central issue in structure-based drug design.Energetics of the Binding Process Dissecting the binding free energy into
8、 componentsFInteraction energy between ligand and protein(enthalpic)FOverall loss in entropy due to association(entropic)FHydrophobic effect(entropic)FEntropy loss due to rotational constraints(entropic)FChanges in conformational energy upon binding (enthalpic)=+Protein-Ligand InteractionsElectrosta
9、tic interactionCoordinate bonding with metal ionVan der Waals interactionHydrogen bondingKinteraction = k1KSB + k2KIB+ k3KVC + k4KVB + k5KHBSCORE equation.constmetalRotorcHydrophobibondHVDWdKKKKKpK Taking account for VDW interaction, hydrogen bonding, hydrophobic interaction, deformation entropy los
10、s and metal-bonding upon protein-ligand binding process.Correlation between the calculated pKd values andthe experimental values of 170 protein-ligand complexesAtomic Binding ScoreThe overall binding affinity can be decomposedinto the contribution of individual atoms.ALOHA!XLOGP: A New Atom-Addition
11、 Method for Calculating Partition CoefficientsRenxiao Wang, Ying Fu, and Luhua LaiInstitute of Physical Chemistry, Peking UniversityJ.Chem.Inf.Comput.Sci. 1997, 37, 615-621Using 80 atom types (C, H, O, N, S, P, halogens)and 5 correction factorsijjjiibmanPlogCorrelation between the calculated logP va
12、lues 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.-Aided Mol. Design 13:547-562(1999)(1) Docking算法在药物设计中的作用。(2) PRO_LEADS采用何种方法进行配体的柔性对接？(3) 结合亲合性的计算方法及合理性？(4) 在受体与配体的对接过程中应该考虑哪些构象变化（分子柔性），现有的程序可以处理哪些，哪些构象变化是目前尚未考虑的？针对所存在的问题可能采取的策略？(5) 三种不同蛋白对接研究的不同结果是什么？
