Testing inhomogeneous solvation theory in structure-based ligand discovery

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.