Identifying Protein Binding Sites and Optimal Ligands

We describe a method for locating and characterizing the optimal binding site for ligands on the surface of a protein of known structure. The method identifies the contiguous constant-volume region with the most favorable binding affinity using a grid-based representation of interaction energies between the ligand and protein. By scanning through a range of ligand volumes and following the value of the average binding affinity per unit volume, optimal binding sites may be identified and ranked, and the ideal size for a ligand may be identified for each binding site. For use in drug design, the ideal volumes identify regions of primary binding affinity and regions of suboptimal binding strength. We demonstrate the utility of the method in design of inhibitors for HIV-1 protease.