Belkina N V, Skvortsov V S, Ivanov A S, Archakov A I
Institute of Biomedical Chemistry, Moscow, Russia.
Vopr Med Khim. 1998 Sep-Oct;44(5):464-73.
The substances inhibiting cytochrome P450 1A2 (CYP1A2) represent a perspective class of new drugs, which application in clinical practice can become the important part in preventive maintenance in oncology. The present work is devoted to computer modelling of 3-D structure of CYP1A2 and searching of new inhibitors by database mining. The modelling of CYP1A2 was done based on homology with 4 bacterial cytochromes P450 with known 3-D structure. For optimization of CYP1A2 active site structure the models of its complexes with characteristic substrates (caffeine and 7-ethoxyresorufin) were designed. These complexes were optimized by molecular dynamics simulation in water. The models of 24 complexes of CYP1A2 with known ligands with known Kd were designed by means of DockSearch and LeapFrog programs. 3D-QSAR model with good predictive force was created based on these complexes. On a final stage the search of knew CYP1A2 ligands in testing database (more than 23.000 substances from database Maybridge and 112 known CYP1A2 ligands from database Metabolite, MDL) was executed. 680 potential ligands of CYP1A2 with Kd values, comparable with known ones were obtained. This number has included 73 compounds from 112 known ligands, introduced in tested database as the internal control.
抑制细胞色素P450 1A2（CYP1A2）的物质代表了一类有前景的新型药物，其在临床实践中的应用可能成为肿瘤预防的重要组成部分。目前的工作致力于CYP1A2三维结构的计算机建模以及通过数据库挖掘寻找新的抑制剂。CYP1A2的建模是基于与4种具有已知三维结构的细菌细胞色素P450的同源性进行的。为了优化CYP1A2活性位点结构，设计了其与特征底物（咖啡因和7-乙氧基试卤灵）的复合物模型。这些复合物在水中通过分子动力学模拟进行了优化。借助DockSearch和LeapFrog程序设计了CYP1A2与24种已知配体且已知解离常数（Kd）的复合物模型。基于这些复合物创建了具有良好预测能力的三维定量构效关系（3D-QSAR）模型。在最后阶段，在测试数据库（来自Maybridge数据库的超过23000种物质以及来自Metabolite、MDL数据库的112种已知CYP1A2配体）中搜索新的CYP1A2配体。获得了680种CYP1A2的潜在配体，其Kd值与已知配体相当。这个数字包括了作为内部对照引入测试数据库的112种已知配体中的73种化合物。
