A novel approach for enhancing the potency of kinase inhibitors using topological water networks

Optimizing the potency of kinase inhibitors remains a major challenge due to the structural conservation of kinase binding pockets. While several computational methods have been developed to address this issue, most overlook the crucial role of water molecules within the binding site. Our research aims to address this gap by examining topological water networks (TWNs) within the target protein. We identified specific TWN-derived patterns in kinase binding sites which align with known crystallographic kinase fragments. Our findings reveal the potential of TWNs to significantly improve the identification and optimal placement of promising fragments within protein binding sites. Here, we propose TWN-based fragment growing (TWN-FG) method that enhances kinase inhibitor potency by leveraging the topological characteristics of hydration networks. TWN-FG successfully explains structure–activity relationship (SAR) trends of known kinase inhibitors and has been applied to design and synthesize a potent mixed lineage kinase 1 (MLK1) inhibitor. The source code is available at https://github.com/RgJeoung/TWN-FG to support further research and application. We introduce TWN-FG, a novel fragment growing method for the potency optimization of kinase inhibitors. This method examines the target protein's binding pocket by identifying TWNs and suggests optimal regions for fragment growth based on observed TWN-derived hydration patterns. Furthermore, this method aids in selecting favorable substituents, providing valuable guidance in ligand design. We believe that TWN-FG method will serve as a useful tool for medicinal chemists in their drug discovery efforts.