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

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 TWNFS method package is available on GitHub at https://github.com/pkj0421/TWN-FS.

Automated summary

Fragment-based drug discovery (FBDD) is an effective method for generating diverse and novel drug candidates. This study introduces a novel screening method, TWN-FS, based on topological water networks (TWNs), which provides valuable insights into fragment localization and shape within protein binding sites.