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

@article{citeulike:2762966, 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.}, author = {Sherman, Woody and Tidor, Bruce}, citeulike-article-id = {2762966}, citeulike-linkout-0 = {http://www.blackwell-synergy.com/doi/abs/10.1111/j.1747-0285.2008.00659.x}, citeulike-linkout-1 = {http://dx.doi.org/10.1111/j.1747-0285.2008.00659.x}, doi = {10.1111/j.1747-0285.2008.00659.x}, journal = {Chemical Biology \& Drug Design}, keywords = {drug\_discovery, protein\_ligand}, number = {5}, pages = {387--407}, posted-at = {2008-07-08 01:14:49}, priority = {2}, title = {Novel Method for Probing the Specificity Binding Profile of Ligands: Applications to HIV Protease}, url = {http://dx.doi.org/10.1111/j.1747-0285.2008.00659.x}, volume = {71}, year = {2008} }

TY - JOUR ID - citeulike:2762966 L3 - citeulike-article-id:2762966 N2 - 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. IS - 5 JF - Chemical Biology & Drug Design EP - 407 TI - Novel Method for Probing the Specificity Binding Profile of Ligands: Applications to HIV Protease VL - 71 SP - 387 KW - drug_discovery KW - protein_ligand AU - Sherman, Woody AU - Tidor, Bruce PY - 2008/// UR - http://dx.doi.org/10.1111/j.1747-0285.2008.00659.x ER -