Aug 2026· ACS Physical Chemistry Au· 0 citations· 82 references
TL;DR
HydroDock is extended to challenging targets with open binding pockets, populated by highly mobile water molecules that are the most troublesome for drug design, and improved docking accuracy with increases of 28% (10%) in median structural (and ranking) performance.
Abstract
Correctly positioning water molecules at the drug-target interface is a major challenge in structure-based drug design. Predicting how water structure reorganizes during drug docking into the target pocket is particularly difficult. Previously, a molecular dynamics-based protocol, HydroDock, was introduced and tested for docking small ligands into hydrated ion channels. Here, we extend the applicability of HydroDock to challenging targets with open binding pockets, populated by highly mobile water molecules that are the most troublesome for drug design. HydroDock improved docking accuracy, with increases of 28% (10%) in median structural (and ranking) performance. The comparison with other methods showed that HydroDock is a robust solution, even for problematic systems in which docking without explicit water molecules failed to find the correct drug-binding mode.
Assessment of pose prediction methods when the bound structure of a reference ligand is known and the likely binding mode(s) of a related compound are needed, and this work focuses on cases where the new compound has multiple potential binding modes.
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This study performed mixed-solvent molecular dynamics simulations using four types of probe molecules to improve the accuracy of large-scale VS and proposed a method for the modification of the docking scoring function for five selected atom classifications (XS_types).
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Scaffold-Guided Structure Refinement is presented, leveraging information on known binders within ligand series targeting a specific protein, based on the observation that shared molecular scaffolds among binders exhibit conserved binding modes.
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A novel and simple hydrophobicity scale derived from the Kyte-Doolittle hydrophobicity scale leads to a performance improvement of around 10% in ranking, cluster quality and water recovery at the interface compared with the statistics-based original solvated docking protocol.
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ProtLID2.0 is presented, a residue-specific pharmacophore framework that generates coordinate-based interaction preferences from molecular dynamics simulations of single-residue probes at receptor interfaces and uses these preferences to score docked complexes and identify cognate ligands.
S. Grudman, Christopher Mcclain, A. Fiser· Journal of Chemical Informat...· 0 citations
