Novel Method for Probing the Specificity Binding Profile of Ligands: Applications to HIV Protease

Abstract

A detailed understanding of factors influencing the binding specificity of a ligand to a set of desirable targets and undesirable decoys is a key step in the design of potent and selective therapeutics. We have developed a general method for optimizing binding specificity in ligand–receptor complexes based on the theory of electrostatic charge optimization. This methodology can be used to tune the binding of a ligand to a panel of potential targets and decoys, along the continuum from narrow binding to only one partner to broad binding to the entire panel. Using HIV‐1 protease as a model system, we probe specificity in three distinct ways. First, we probe interactions that could make the promiscuous protease inhibitor pepstatin more selective toward HIV‐1 protease. Next, we study clinically approved HIV‐1 protease inhibitors and probe ways to broaden the binding profiles toward both wild‐type HIV‐1 protease and drug‐resistant mutants. Finally, we study a conformational ensemble of wild‐type HIV‐1 protease to ‘design in’ broad specificity to known drugs before resistance mutations arise. The results from this conformational ensemble were similar to those from the drug‐resistant ensemble, suggesting the use of a conformational wild‐type ensemble as a tool to develop escape‐mutant‐resistant inhibitors.