Nicklaus M C, Neamati N, Hong H, Mazumder A, Sunder S, Chen J, Milne G W, Pommier Y
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
J Med Chem. 1997 Mar 14;40(6):920-9. doi: 10.1021/jm960596u.
Starting from a known inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase (IN); caffeic acid phenethyl ester (CAPE), a putative three-point pharmacophore for binding of inhibitors to IN was derived. This pharmacophore was used to search the National Cancer Institute three-dimensional (3D) structural database. Out of the open, nonproprietary part of this database, comprising approximately 200000 compounds, 267 structures were found to match the pharmacophore in at least one conformation, and 60 of those were tested in an in vitro assay against HIV-1 IN. Out of these, 19 were found to inhibit both the 3'-processing and strand transfer of IN at micromolar concentrations. In order to test the validity of this pharmacophore, a small 3D database of 152 published IN inhibitors was built. A search in this database yielded a statistically significant correlation of the presence of this pharmacophore and the potency of the compounds. An automated pharmacophore identification procedure performed on this set of compounds provided additional support for the importance of this pharmacophore for binding of inhibitors to IN and hinted at a possible second pharmacophore. The role of aromatic moieties in the binding of ligands to HIV-1 IN through interactions with divalent metal cations, which are known to be necessary for activity of the enzyme, was explored in ab initio calculations.
从已知的人类免疫缺陷病毒1型（HIV-1）整合酶（IN）抑制剂咖啡酸苯乙酯（CAPE）出发，推导了一种抑制剂与IN结合的假定三点药效团。该药效团用于搜索美国国立癌症研究所的三维（3D）结构数据库。在该数据库的公开、非专有部分（约200000种化合物）中，发现267种结构至少在一种构象下与药效团匹配，其中60种在针对HIV-1 IN的体外试验中进行了测试。其中，19种被发现在微摩尔浓度下可抑制IN的3'-加工和链转移。为了测试该药效团的有效性，构建了一个包含152种已发表的IN抑制剂的小型3D数据库。在该数据库中的搜索得出该药效团的存在与化合物效力之间具有统计学上的显著相关性。对这组化合物进行的自动药效团识别程序为该药效团对于抑制剂与IN结合的重要性提供了额外支持，并暗示可能存在第二个药效团。通过从头计算，研究了芳香基团通过与二价金属阳离子相互作用在配体与HIV-1 IN结合中的作用，已知二价金属阳离子是该酶活性所必需的。
