A genetic algorithm for flexible molecular overlay and pharmacophore elucidation
A genetic algorithm for flexible molecular overlay and pharmacophore elucidation
复制标题
DOI：
10.1007/bf00124324
复制
发表时间：
1995-12-01
影响因子：
3.5
通讯作者：
Glen, RC
中科院分区：
文献类型：
--
作者：
Jones, G;Willett, P;Glen, RC
遗传算法（GA）已被开发用于柔性分子组的叠加。分子由染色体表示，该染色体编码绕柔性键的旋转角度以及分子对中氢键供体质子、受体孤对和环中心特征之间的映射。数据集中具有最少特征的分子被用作模板，剩余的分子被拟合到该模板上，以最大化结构等价性。 GA的适应度函数是以下各项的加权组合：（i）以这种方式叠加的特征的数量和相似度； (ii) 覆盖层的体积积分； (iii) 由染色体编码的扭转角定义的分子构象的范德华能量。该算法已应用于许多药效团阐明问题，即血管紧张素 II 受体拮抗剂、亮氨酸脑啡肽和混合吗啡分子、5-HT1D 激动剂、苯二氮卓受体配体、5-HT3 拮抗剂、多巴胺 D-2 拮抗剂、多巴胺再摄取阻滞剂和 FKBP12 配体。由此产生的药效团快速生成，并且与通过其他方法获得的药效团非常一致。
A genetic algorithm (GA) has been developed for the superimposition of sets of flexible molecules. Molecules are represented by a chromosome that encodes angles of rotation about flexible bonds and mappings between hydrogen-bond donor proton, acceptor lone pair and ring centre features in pairs of molecules. The molecule with the smallest number of features in the data set is used as a template, onto which the remaining molecules are fitted with the objective of maximising structural equivalences. The fitness function of the GA is a weighted combination of: (i) the number and the similarity of the features that have been overlaid in this way; (ii) the volume integral of the overlay; and (iii) the van der Waals energy of the molecular conformations defined by the torsion angles encoded in the chromosomes. The algorithm has been applied to a number of pharmacophore elucidation problems, i.e., angiotensin II receptor antagonists, Leu-enkephalin and a hybrid morphine molecule, 5-HT1D agonists, benzodiazepine receptor ligands, 5-HT3 antagonists, dopamine D-2 antagonists, dopamine reuptake blockers and FKBP12 ligands. The resulting pharmacophores are generated rapidly and are in good agreement with those derived from alternative means.