title: 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.
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, NY 10036, USADepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, USAComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, USADepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, USADepartment of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, USA.
authors.forename: Woody
authors.initials: W
authors.lastname: Sherman
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, NY 10036, USADepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, USAComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, USADepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, USADepartment of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Tidor
mesh_terms: D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D008024:Ligands; D008722:Methods; D008968:Molecular Conformation; D011485:Protein Binding; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D017320:HIV Protease Inhibitors; D008024:Ligands; D016333:HIV Protease