计算机辅助药物设计CADD-QSAR.pptVIP

* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * Hammett方程中，k代表反应速率常数或平衡常数。 * * * * * * * * * * * * * * * * * 内 容 背景知识 QSAR常用的参数 建立QSAR的统计方法 2D-QSAR 3D-QSAR 3D-QSAR应用实例 * 80年代以来，在QSAR研究中，陆续出现了几种考虑生物活性分子与受体结合三维结构性质的研究方法，统称三维定量构效关系(3D-QSAR)。 3D-QSAR与上述2D-QSAR的最大不同之处，在于它们考虑生物活性分子三维构象性质，在QSAR分析中引进了与生物活性分子的三维结构信息有关的量作为变元(descriptor)。与2D-QSAR相比，这些方法能较为精确地反映生物活性分子与受体作用的图象，更深刻地揭示药物?受体相互作用的机理，因而逐渐引起了药物化学家的重视。 Hopfinger等(1980)的分子形状分析(molecular shape analysis, MSA)； Crippen等(1979)的距离几何（distance geometry 3D-QSAR,DG）方法； Cramer 等(1988)的比较分子场分析（comparative molecular field analysis, CoMFA）方法 Klebe (1994)的比较分子相似因子分析(comparative molecular similarity index analysis, CoMSIA)方法 虚拟受体方法(PR) * * CoMFA methodology Training set design Training set alignment Molecular Interaction Fields calculation Statistical analyses Interpretation Graphical representation 3D-QSAR: CoMFA * 3D-QSAR: CoMFA Training set design The training set should contain a wide range of structurally diverse compounds Both the range and the distribution of biological data are of great importance * Training set design Set 1 : 16 compounds Set 4 : 3 compounds Set 2 : 7 compounds Set 5 :12 compounds Set 3 : 18 compounds Set 6 : 22 compounds Set 7 : 21 compounds * Sets 4, 5 and 7: not enough active (4,5) or inactive (7) compounds. Sets 1, 2 and 3: poor distribution of biological activities. Set 6: Broad range and relatively well distributed biological activities Training set design * Training set design Statistical analyses for training set 6 * Training set design Statistical analyses for training set 1, 3, 5 and 6 Q2 from SAMPLS using a Leave One Out (LOO) procedure * Training set design By combining sets 1, 2 and 3, no CoMFA model was found, presumably due to the poor distribution of activities. However, by combining set 4 with either set 1, 2 or 3, CoMFA produced surprisingly good statistical models. * Training set design Statistics are mar