Robust Ligand Docking into Challenging Hydrated Binding Pockets

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.