Linker Library:基于几何特征的骨架跃迁片段库

Linker Library:Fragment Library for Scaffold Hopping Based on Geometric Features

骨架跃迁是目前应用最广泛的药物设计策略之一,但是现有骨架跃迁方法产生的化合物大多为已报道的先导化合物的衍生物或类似物,化学结构缺乏新颖性。针对现有骨架跃迁方法的局限性,提出了一种保持药效团与骨架之间的相对距离和角度不变的骨架跃迁策略,构建一个包含骨架几何特征的linker片段库:Linker Library。该片段库可以根据骨架中心到连接点之间距离和角度,推荐结构新颖且可保持官能团相对位置的片段,有助于指导化合物的骨架跃迁并加速药物发现进程。

In order to improve the success rate of new drugs,major pharmaceutical companies are committed to developing new strategies and technologies for Computer Aided Drug Design(CADD).Scaffold hopping is one of the most commonly used strategies for discovering lead compounds.However,most of the lead compounds generated by existing scaffold hopping strategies are derivatives or analogs of reported lead compounds that lack novelty.To improve structure novelty,we proposed a geometry-based scaffold hopping strategy,which took the idea for the first time to keep the relative distances and angles unchanged between pharmacophores and skeleton.Thus,a linker library for scaffold hopping based on geometric features was constructed.The original compounds of the linker library were derived from Cambridge Structural Database(CSD),and which were broken into fragments by Retrosynthetic Combinatorial Analysis Procedure(RECAP).After a series of screening and processing,we designed a linker library containing 1587020 fragments with 2~4 connection points.There was a case about Skepinone-L,a selective inhibitor of MAPK11,which verified the usefulness of the linker library.Based on the distances and angles between the center to connected points of the skeleton,the linker library could recommend fragments with novel scaffolds to maintain the relative position of pharmacophores,which is beneficial to guide scaffold hopping and accelerate the process of drug discovery.