Abstract
Examining the potential for electrostatic complementarity between a ligand and a receptor is a useful technique for rational drug design, and can demonstrate how a system prioritizes interactions when allowed to optimize its charge distribution. In this computational study, we implemented the previously developed, continuum solvent‐based charge optimization theory with a simple, quadratic programming algorithm and the UHBD Poisson–Boltzmann solver. This method allows one to compute the best set of point charges for a ligand or ligand region based on the ligand and receptor shape, and the receptor partial charges, by optimizing the binding free energy obtained from a continuum‐solvent model. We applied charge optimization to a fragment of the heat‐stable protein kinase inhibitor (PKI) of protein kinase A (PKA), to three flavopiridol inhibitors of CDK2, and to cyclin A which interacts with CDK2 to regulate the cell cycle. We found that a combination of global (involving every charge) and local (involving only charges in a local region) optimization can give useful hints for designing better inhibitors. Although some parts of an inhibitor may already contribute significantly to binding, we found that they could still be the most important targets for modifications to obtain stronger binders. In studying the binding of flavopiridol inhibitors to CDK2, comparable binding affinity could be obtained regardless of whether the net charges of the inhibitors were constrained to −2, −1, 0, 1, or 2 during the optimization. This provides flexibility in inhibitor design when a certain net charge of the inhibitor is desired in addition to strong binding affinity. For the study of the PKA–PKI and CDK2–cyclin A interfaces, we identified residues whose charge distributions are already close to optimal and those whose charge distributions could be refined to further improve binding. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1416–1429, 2004