Sensitivity Analysis and Charge-Optimization for Flexible Ligands: Applicability to Lead Optimization.

Sensitivity analysis and charge-optimization have been suggested as methods to guide the optimization of lead compounds in early-stage drug discovery. However, applications to date have been restricted by the simplifying assumption of a rigid ligand. The present study applies both formalisms to the case of a flexible ligand in a model application to an HIV-protease inhibitor. The results suggest that sensitivity analysis is a fast and robust method for guiding charge changes in both a rigid and a flexible ligand, although its accuracy is limited by the fact that it represents a linear approximation. The more complete quadratic analysis provided by charge-optimization produces unexpected results when the ligand is considered to be flexible. For example, it can yield atomic charges which powerfully stabilize the bound conformation of the ligand relative to the conformation assumed for the free state, thus markedly destabilizing the assumed free conformation. Such results are traceable to the fact that the energy matrix possesses negative eigenvalues. However, optimizing charges under the assumption that the ligand does not change conformation upon binding leads to a set of charges that robustly improve affinity, even when the free conformation is later allowed to vary. Thus, both sensitivity analysis and charge-optimization appear to be useful techniques.