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.
Ažbeta Kubincová, S. S. Çınaroğlu, Jianna Ongsioco et al.· Journal of Chemical Informat...· 0 citations
Structure-based virtual screening (VS) is widely used for the computational selection of drug candidates from compound libraries. Protein–ligand docking calculations are often performed as key steps in the early stages of this process. However, current docking calculations have limited accuracy. Thus, improvements are needed to more efficiently identify promising drug candidates. In this study, we performed mixed-solvent molecular dynamics (MSMD) simulations using four types of probe molecules to improve the accuracy of large-scale VS. We proposed a method for the modification of the docking scoring function for five selected atom classifications (XS_types). This approach integrated the grid free energy derived from the relevant atoms across the probe molecules. VS experiments conducted on nine target proteins showed improved accuracy, with the average EF1% increasing from 6.65 to 7.36. Our method may facilitate drug discovery with higher accuracy than that of conventional methods.
Unknown authors· Journal of Chemical Informat...· 0 citations
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.
J. Pletzer-Zelgert, Matthias Rarey, Bernd Kuhn· Journal of Medicinal Chemist...· 0 citations
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
