Jayatilleke P R, Nair A C, Zauhar R, Welsh W J
Department of Chemistry and Center for Molecular Electronics, University of Missouri-St. Louis, St. Louis, Missouri 63121, USA.
J Med Chem. 2000 Nov 16;43(23):4446-51. doi: 10.1021/jm9905357.
A theoretical study was performed on a set of 38 human immunodeficiency type 1 (HIV-1) protease inhibitors that are structurally similar to the AIDS drug Indinavir. Comparison between the computed binding energies and experimental activity data (pIC(50)) found a high degree of correlation (r(2)() = 0.82). Three-dimensional quantitative structure-activity relationship (3D-QSAR) models using comparative molecular field analysis (CoMFA) yielded predicted activities that were in excellent agreement with the corresponding experimentally determined values. Inclusion of the calculated enzyme-inhibitor binding energy as an additional descriptor in the CoMFA model yielded a significant improvement in the internal predictive ability of our model (q(2)() = 0.45 to q(2)() = 0.69). Separate CoMFA models were constructed to evaluate the influence of different alignment schemes (Atom Fit and Field Fit) and different partial atomic charge assignment schemes (Discover CVFF, Gasteiger-Marsili, and AM1-ESP) on the statistical quality of the models.
对一组38种与艾滋病药物茚地那韦结构相似的1型人类免疫缺陷病毒（HIV-1）蛋白酶抑制剂进行了理论研究。计算得到的结合能与实验活性数据（pIC(50)）之间的比较发现了高度相关性（r(2) = 0.82）。使用比较分子场分析（CoMFA）的三维定量构效关系（3D-QSAR）模型得出的预测活性与相应的实验测定值高度吻合。在CoMFA模型中纳入计算得到的酶-抑制剂结合能作为一个额外的描述符，使我们模型的内部预测能力有了显著提高（q(2)从0.45提高到0.69）。构建了单独的CoMFA模型，以评估不同对齐方案（原子拟合和场拟合）以及不同部分原子电荷分配方案（Discover CVFF、Gasteiger-Marsili和AM1-ESP）对模型统计质量的影响。
