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TWN-FS方法:一种用于药物发现的新型片段筛选方法。

TWN-FS method: A novel fragment screening method for drug discovery.

作者信息

Yoon Hye Ree, Park Gyoung Jin, Balupuri Anand, Kang Nam Sook

机构信息

Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, South Korea.

出版信息

Comput Struct Biotechnol J. 2023 Sep 29;21:4683-4696. doi: 10.1016/j.csbj.2023.09.037. eCollection 2023.

Abstract

Fragment-based drug discovery (FBDD) is a well-established and effective method for generating diverse and novel hits in drug design. Kinases are suitable targets for FBDD due to their well-defined structure. Water molecules contribute to structure and function of proteins and also influence the environment within the binding pocket. Water molecules form a variety of hydrogen-bonded cyclic water-ring networks, collectively known as topological water networks (TWNs). Analyzing the TWNs in protein binding sites can provide valuable insights into potential locations and shapes for fragments within the binding site. Here, we introduce TWN-based fragment screening (TWN-FS) method, a novel screening method that suggests fragments through grouped TWN analysis within the protein binding site. We used this method to screen known CDK2, CHK1, IGF1R and ERBB4 inhibitors. Our findings suggest that TWN-FS method has the potential to effectively screen fragments. The TWN-FS method package is available on GitHub at https://github.com/pkj0421/TWN-FS.

摘要

基于片段的药物发现(FBDD)是一种成熟且有效的方法,可在药物设计中产生多样且新颖的活性分子。激酶因其明确的结构而成为FBDD的合适靶点。水分子对蛋白质的结构和功能有贡献,并且还会影响结合口袋内的环境。水分子形成各种氢键连接的环状水环网络,统称为拓扑水网络(TWNs)。分析蛋白质结合位点中的TWNs可以为结合位点内片段的潜在位置和形状提供有价值的见解。在此,我们介绍基于TWN的片段筛选(TWN-FS)方法,这是一种新颖的筛选方法,通过对蛋白质结合位点内的TWN进行分组分析来推荐片段。我们使用此方法筛选了已知的CDK2、CHK1、IGF1R和ERBB4抑制剂。我们的研究结果表明,TWN-FS方法有潜力有效筛选片段。TWN-FS方法包可在GitHub上获取,网址为https://github.com/pkj0421/TWN-FS。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f9/10568351/499407996773/ga1.jpg

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