G Protein-Coupled Receptors (GPCRs) are the largest protein family in the human genome, and as key regulators of many physiological processes, are also the family most often targeted by small molecule therapeutics. The wealth of co-crystal structures and biophysical data for GPCR-ligand complexes now available allows for �high-end� ligand design, taking into account explicit water networks as an additional dimension for structure based drug design. We will present structural and kinetic data for several small molecule GPCR binders. Using computational models of explicit water structure and dynamics we will rationalize this kinetic data. Explicit water structure is often the missing dimension that can be used to explain puzzling SAR data, and must be taken into account for prospective lead optimization. The use of explicit water networks to rationalize and predict small molecule energetics, potency and kinetics in the context of GPCR binding will likely contribute to safer and more efficacious drugs.

GPCR drug-binding kinetics: Insights from explicit water network modeling

248th National Meeting (2014)

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