There is increasing evidence that water molecules can be crucial in understanding protein-ligand binding and kinetics. Water mediated interactions of ligands with biological targets have always been considered important. However, before the availability of high resolution X-ray data a thorough interpretation of their role and an assessment of the predictive capability of computational methods was a very difficult task. This is particularly important in drug discovery, since binding energy changes from just the perturbation of the water network can explain structure-activity relationships, which may be difficult to interpret on the basis of only ligand-protein structure. Computational approaches to generate and score water networks are now available; in this work, we present an approach based on molecular dynamics coupled with enhanced sampling techniques which is able to accelerate the (de)hydration of a protein binding site and aims at achieving a faster identification and characterization of persistent water molecules in or around a protein binding site.We show the results of our approach on targets of pharmaceutical relevance and in particular on two representatives of the A2A adenosine receptor subclass: the A2aAR-BRIL,[1] for which a high resolution crystallographic structure including waters is available, and the thermally stabilized adenosine A2A construct A2A-StaR2,[2] the water network of which has been discussed in several complexes with potential drugs.[1] Liu et al. Science 337(6091):232-6, 2012[2] Congreve et al. J. Med. Chem. 55, 1898-1903, 2012

Role of hydration in protein-ligand binding studied via enhanced sampling molecular dynamics approaches

248th National Meeting (2014)

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