The ability to calculate full water networks and estimate the relative energy of each water molecule is a recent major breakthrough in computational drug design. Water is now considered to be a key component for design along with the ligand and the protein. Initial applications focused on potency and druggability and clearly waters need to be considered during docking and scoring. Water-mediated ligand selectivity enables designs where a smaller vs larger molecule can be used, with potentially better drug-like properties. Waters have been shown in many G protein-coupled receptor (GPCR) X-ray structures to play important roles and at times to mediate all polar interactions.<br/>The residence time of a ligand-protein complex is a critical aspect in determining biological effects in vivo, and recently we have investigated off-rate kinetics prediction and have had encouraging results. It can for some series be possible to have a simple model looking just at trapped water energetics, but as the unbinding event is complex with multiple possible paths and we have developed a molecular dynamics (MD) based approach to decode the role of water dynamics in ligand-protein unbinding. It is based on adiabatic-bias MD and metadynamics, and the protocol can provide actionable working hypotheses that are applicable to the rational optimisation of ligand binding kinetics in a drug discovery program.<br/>Results of these methods for predicting off-rate kinetics will be presented, together with examples of the critical role of waters in design, for a variety of GPCR targets including the multiple ligand structures from the StaR® (Stabilised Receptor) technology..

Water: A small but revolutionary molecule that together with GPCR X-ray structures enables new design approaches for kinetics, selectivity and potency

251st National Meeting (2016)

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