The application of WaterMap-guided structure-based virtual screening in novel drug discovery

ABSTRACTIntroduction Nowadays, it is widely accepted that water molecules play a key role in binding a ligand to a molecular target. Neglecting water molecules in the process of molecular recognition was the result of several failures of the structure-based drug discovery campaigns. The application of WaterMap, in particular WaterMap-guided molecular docking, enables the reasonably accurate and quick description of the location and energetics of water molecules at the ligand–protein interface.Areas covered In this review, the authors shortly discuss the importance of water in drug design and discovery and provide a brief overview of the computational approaches used to predict the solvent-related effects for the purposes of presenting WaterMap in the context of other available techniques and tools. A concise description of WaterMap concept is followed by the presentation of WaterMap-assisted virtual screening literature published between 2013 and 2023.Expert opinion In recent years, WaterMap software has been extensively used to support structure-based drug design, in particular structure-based virtual screening. Indeed, it is a useful tool to rescore docking results considering water molecules in the binding pocket. Although WaterMap allows for the consideration of the dynamic behavior of water molecules in the binding site, for best accuracy, its application in conjunction with other techniques such as molecular mechanics–generalized Born surface area of FEP (Free Energy Perturbation) is recommended.KEYWORDS: Computer-aided drug designstructure-based drug discoveryvirtual screeningwater in drug designWaterMap Article highlights WaterMap has been extensively used to support structure-based drug design and structure-based virtual screening;WaterMap application may help to design more potent ligands by taking into consideration water molecules in the binding pocket;WaterMap allows us to consider dynamic aspects of water molecules in the binding site;The accuracy of water position or more often water energy may be in some cases unsatisfactory.For best results, WaterMap may be supported by other techniques such as MM-GB/SA or FES.Declaration of interestThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThe authors are funded by the Uniwersytet Medyczny w Lublinie under under the statutory grant DS33 (to A.A.K.).