Bridging water molecules are often found in protein-ligand complexes that mediate interactions between the ligand and surrounding residues. In drug refinement, it has been an effective strategy to displace such waters with polar functionalities in rationally designed ligands (<i>e.g.</i> cyclic urea inhibitors developed for HIV-1 protease) in order to improve binding affinity. Another strategy to potentially improve potency is to coordinate bridging water molecules (to maintain the favorable water-mediated interactions) with novel ligands. In the present study we report an interaction energy-based computational approach to specifically identify bridging water molecules and to further incorporate (displace or coordinate) them in virtual screens. Solvated molecular footprints (per-residue interaction energy) are employed to drive water displacement. The proposed approach has been tested on five disease-related complexes (four crystallographic structures and one homology model) and both previously reported and novel bridging water molecules have been identified. Results from several small-scale virtual screens will also be presented to identify novel ligands with water displacement or coordination as proof of concept.

Computational approach to energetically identify bridging water molecules and to incorporate them in virtual screens

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.