Gussio R, Pattabiraman N, Zaharevitz D W, Kellogg G E, Topol I A, Rice W G, Schaeffer C A, Erickson J W, Burt S K
Frederick Biomedical Supercomputing Center, National Cancer Institute-FCRDC, Frederick, Maryland 21702, USA.
J Med Chem. 1996 Apr 12;39(8):1645-50. doi: 10.1021/jm9508088.
Several molecular modeling techniques were used to generate an all-atom molecular model of a receptor binding site starting only from Ca atom coordinates. The model consists of 48 noncontiguous residues of the non-nucleoside binding site of HIV-1 reverse transcriptase and was generated using a congeneric series of nevirapine analogs as structural probes. On the basis of the receptor-ligand atom contacts, the program HINT was used to develop a 3D quantitative structure activity relationship that predicted the rank order of binding affinities for the series of inhibitors. Electronic profiles of the ligands in their docked conformations were characterized using electrostatic potential maps and frontier orbital calculations. These results led to the development of a 3D stereoelectronic pharmacophore which was used to construct 3D queries for database searches. A search of the National Cancer Institute's open database identified a lead compound that exhibited moderate antiviral activity.
几种分子建模技术被用于仅从钙原子坐标开始生成受体结合位点的全原子分子模型。该模型由HIV-1逆转录酶非核苷结合位点的48个不连续残基组成，并且是使用一系列奈韦拉平类似物作为结构探针生成的。基于受体-配体原子接触，使用程序HINT开发了三维定量构效关系，该关系预测了该系列抑制剂的结合亲和力的排序。使用静电势图和前沿轨道计算对配体对接构象中的电子轮廓进行了表征。这些结果导致开发了一种三维立体电子药效团，该药效团用于构建数据库搜索的三维查询。对美国国立癌症研究所的开放数据库进行搜索，确定了一种具有中等抗病毒活性的先导化合物。
