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Area of Science:

  • Computational chemistry
  • Structural biology
  • Drug discovery

Background:

  • Binding-site water displacement upon ligand recognition is crucial but often overlooked in structure-based drug discovery.
  • Inhomogeneous Solvation Theory (IST) accounts for solvation effects, but experimental validation at atomic resolution is lacking.

Purpose of the Study:

  • To experimentally validate the grid-based GIST method for its impact on ligand discovery, geometry, and water structure.
  • To assess GIST's performance in prospective docking screens.

Main Methods:

  • Implementation of a grid-based GIST method within molecular docking.
  • Retrospective and prospective docking of large compound libraries.
  • Experimental validation of docked ligands through binding assays and X-ray crystallography.

Main Results:

  • GIST showed modest improvement in retrospective enrichment but did not disrupt performance.
  • Prospective docking with GIST prioritized 13/14 experimentally validated binders, while deprioritized compounds did not bind.
  • Crystal structures revealed GIST-predicted ligand geometries in 6/9 complexes, with improved pose accuracy in one case.

Conclusions:

  • The GIST water-displacement term significantly enhances hit rates and ligand geometry prediction in docking screens.
  • While effects can be subtle, GIST offers a valuable tool for improving ligand discovery.
  • Further controlled studies are warranted to explore GIST's impact in diverse drug-binding sites.