Water in drug design: pitfalls and good practices

Structure-based drug design relies on optimizing drug-target interactions and blocking harmful pathophysiological events at the atomic level. Such events of the human body are modulated by water acting either as a medium or an individual partner in molecular interactions. A precise understanding of the modulatory mechanisms of water is essential for a successful drug design.

The present review discusses different topographical and networking situations that result in radically different roles of water, a root of various pitfalls of drug design. The review surveys good practices for tackling the problems of determining water structure at atomic resolution. Techniques for quantifying the effects of bulk, networking, and individual water molecules on the stability of drug-target complexes are also discussed. The article is based on a literature search using the PubMed, Web of Science, and Google Scholar databases.

With advances in rapid computational algorithms and a better understanding of the physicochemical machinery of complex formation, theoretical approaches have resulted in elegant and cost-effective tools that fill the knowledge gaps left by the limited experimental methods. Overcoming the technical pitfalls of drug design, water transforms from a frustrating challenge into a handy tool for fine-tuning drug-target interactions.