General distance geometry three-dimensional receptor model for diverse dihydrofolate reductase inhibitors.
General distance geometry three-dimensional receptor model for diverse dihydrofolate reductase inhibitors.
复制标题
多种二氢叶酸还原酶抑制剂的通用距离几何三维受体模型。
DOI：
10.1021/jm00373a016
复制
发表时间：
1984
影响因子：
7.3
通讯作者：
Crippen,GM
中科院分区：
文献类型：
--
作者：
Ghose,AK;Crippen,GM
方法如前所述，基本步骤包括以下步骤：（1）通过连接从晶体学研究中获得的组成片段来构建分子。17（2）假设配体的结合能来自配体的各个原子与受体位点的一些原子的相互作用。根据这个想法，根据配体的哪个原子与哪个位点相互作用，对各种分子的结合模式做出一个工作假设。(3)从配体分子的结构推导出位点的几何构型。这个问题可以用下列任一方法解决：（i）用距离几何算法，2'3（ii）从强抑制剂和弱抑制剂的构象分析中推测出一种活性构象，18或（iii）检查受体结合配体的晶体学结果。[19]位点既可以表示配体中原子与位点结合时的近似位置，也可以表示位点原子或基团的假设或实际位置。在没有高分辨率晶体学数据的情况下，第一种可能性是直接的，但第二种可能性需要配体点和位点的货车范德华半径。即使这样，它也可以位于以配体点为中心的球上的任何地方，其半径是位点和配体点的货车德瓦尔斯半径之和。然而，有些可能性可能会被排除在空间的理由。例如，如果连接到苯环上的氯原子与受体位点相互作用，后者应该远离环。找到该网站的确切位置的优点是，甚至距离依赖的相互作用可以研究。(4)确定各种几何上可能的结合模式，如
MethodsAs before, 2, 3 the basic procedure consists of the following steps:(1) Construct the molecules by joining their con-stituent fragments as obtained from crystallographic studies. 17 (2) Assume that the binding energy of the ligand comes from the interaction of various atoms of the ligand with some atoms of the receptor sites. Following this idea, make a working hypothesis of the binding modes of the various molecules in terms of which atoms of the ligand interact with which site points.(3) Deduce the site ge-ometry from the structure of the ligand molecules. This problem can be solved in either of the following ways:(i) by using the distance geometry algorithm, 2’3 (ii) hypoth-esizing an active conformation derived from the conformational analysis of the strong andweak inhibitors, 18 or (iii) examining the crystallographic results on the recep-tor-bound ligand. 19 A site point either may represent the approximate location of an atom in the ligand when it binds to the site or it may represent the hypothetical or actual location of a site atom or group. Without highresolution crystallographic data, the first possibility is straightforward, but the second requiresthe van der Waals radii of the ligand point and the site point. Even then it may be located anywhere on the sphere centered at the ligand point andwhose radius is the sum of the van der Waals radii of the site point and the ligand point. How-ever, some of the possibilities may be excluded on steric grounds. For example, if a chlorine atom attached to a benzene ring interacts with the receptor site, the latter should be away from the ring. Finding the exact location of the site has the advantage that even the distance de-pendencies of the interaction may be studied.(4) Determine the various geometrically possible binding modes, as