Ligand design by targeting a binding site water
Pierre Matricon, R. Rama Suresh, Zhan‐Guo Gao, Nicolas Panel, Kenneth A. Jacobson, Jens Carlsson
Abstract
agonist with nanomolar activity. Calculation of the thermodynamic profiles resulting from introducing substituents that interacted with or displaced the ordered water showed that the gain of binding affinity was enthalpy driven. Detailed analysis of the energetics and binding site hydration networks revealed that the enthalpy change was governed by contributions that are commonly neglected in structure-based drug optimization. In particular, simulations suggested that displacement of water from a binding site to the bulk solvent can lead to large energy contributions. Our findings provide insights into the molecular driving forces of protein-ligand binding and strategies for rational drug design.