Energetics of displacing water molecules from protein binding sites: consequences for ligand optimization.

ABSTRACT: A strategy in drug design is to consider enhancing the affinity of lead molecules with structural modifications that displace water molecules from a protein binding site. Because success of the approach is uncertain, clarification of the associated energetics was sought in cases where similar structural modifications yield qualitatively different outcomes. Specifically, free-energy perturbation calculations were carried out in the context of Monte Carlo statistical mechanics simulations to investigate ligand series that feature displacement of ordered water molecules in the binding sites of scytalone dehydratase, p38-alphaMAP kinase, and EGFR kinase. The change in affinity for a ligand modification is found to correlate with the ease of displacement of the ordered water molecule. However,

SUBMITTER: Michel J 

PROVIDER: S-EPMC2783447 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature