In Silico Design and Analysis of a Kinase-Focused Combinatorial Library Considering Diversity and Quality.,Journal of Chemical Information and Modeling

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In Silico Design and Analysis of a Kinase-Focused Combinatorial Library Considering Diversity and Quality.
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2020-01-10 , DOI: 10.1021/acs.jcim.9b00841
Yan Yang ₁ , Yanmin Zhang ₁ , Yi Hua ₁ , Xingye Chen ₁ , Yuanrong Fan ₁ , Yuchen Wang ₁ , Li Liang ₁ , Chenglong Deng ₁ , Tao Lu _{1,

2} , Yadong Chen ₁ , Haichun Liu ₁

Affiliation

A structurally diverse, high-quality, and kinase-focused database plays a critical role in finding hits or leads in kinase drug discovery. Here, we propose a workflow for designing a virtual kinase-focused combinatorial library using existing structures. Based on the analysis of known protein kinase inhibitors (PKIs), detailed fragment optimization, fragment selection, fragment linking, and a molecular filtering scheme were defined. Quick recognition of core fragments that can possibly form dual hydrogen bonds with the hinge region of the ATP-pocket was proposed. Furthermore, three diversity and four quality metrics were chosen for compound library analysis, which can be applied to databases with over 30 million structures. Compared with 13 commercial libraries, our protocol demonstrates a special advantage in terms of good skeleton diversity, acceptable fingerprint diversity, balanced scaffold distribution, and high quality, which can work well not only on existing PKIs, but also on four chosen commercial libraries. Overall, the strategy can greatly facilitate the expansion of a desirable chemical space for kinase drug discovery.

中文翻译：

在计算机设计中，考虑了多样性和质量，着重于激酶组合库。

结构多样，高质量且以激酶为重点的数据库在发现激酶药物发现中的命中或线索中起着至关重要的作用。在这里，我们提出了一种使用现有结构设计虚拟激酶为重点的组合库的工作流程。基于对已知蛋白激酶抑制剂（PKI）的分析，定义了详细的片段优化，片段选择，片段连接和分子过滤方案。提出了快速识别可能与ATP口袋的铰链区形成双氢键的核心片段的方法。此外，选择了三个多样性和四个质量指标进行化合物库分析，可将其应用于具有超过3000万个结构的数据库。与13个商业图书馆相比，我们的协议在良好的骨骼多样性方面展示了特殊的优势，可接受的指纹多样性，平衡的脚手架分布和高质量，不仅可以在现有的PKI上而且在四个选定的商业库上都可以很好地工作。总体而言，该策略可以大大促进激酶药物发现所需化学空间的扩展。

更新日期：2020-01-10

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