De Novo Design of Drug-Like Molecules by a Fragment-Based Molecular Evolutionary Approach
De Novo Design of Drug-Like Molecules by a Fragment-Based Molecular Evolutionary Approach
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DOI：
10.1021/ci400418c
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发表时间：
2014-01-01
影响因子：
5.6
通讯作者：
Takahashi, Yoshimasa
中科院分区：
文献类型：
--
作者：
Kawai, Kentaro;Nagata, Naoya;Takahashi, Yoshimasa
本文描述了一种相似性驱动的简单进化方法来生产新药候选分子。该方法的目的是探索在结构上与参考分子相似但不仅在外周链而且在其支架上有所不同的候选分子。该方法采用我们感兴趣的已知活性分子作为参考分子，用于导航巨大的化学空间。参考分子也用于获得种子片段。使用多个连接规则用种子片段和附加片段准备初始的一组单独结构。片段文库优选由与参考分子的靶标相关的已知分子的集合来制备。文库的每个片段都可用于基于片段的突变。所有片段分为三类；环、接头和侧链。通过与片段库的交叉和基于片段的突变产生新的个体。使用我们自己的 GPCR SARfari 片段库进行计算机实验，验证了我们药物发现方法的可行性。
This paper describes a similarity-driven simple evolutionary approach to producing candidate molecules of new drugs. The aim of the method is to explore the candidates that are structurally similar to the reference molecule and yet somewhat different in not only peripheral chains but also their scaffolds. The method employs a known active molecule of our interest a a reference molecule, which is used to navigate a huge chemical space. The reference molecule is also used to obtain seed fragments. An initial set of individual structures is prepared with the seed fragments and additional fragments using several connection rules. The fragment library is preferably prepared from a collection of known molecules related to the target of the reference molecule. Every fragment of the library can be used for fragment-based mutation. All the fragments are categorized into three classes; rings, linkers, and side chains. New individuals are produced by the crossover and the fragment-based mutation with the fragment library. Computer experiments with our own fragment library prepared from GPCR SARfari verified the feasibility of our approach to drug discovery.