Molecular simulations for the evaluation of binding free energies in lead optimization

(Table Presented) The ability to predict, through computer simulation, the free energy of binding between drug-like ligands and their biological target(s) is one of the most difficult yet rewarding tasks in computer-aided drug design (CADD) efforts. Successful and consistent predictions are likely to have a profound effect on the efficiency of hit discovery and lead optimization campaigns. However, the route to achieving this goal is paved with challenges resulting from the complexity of the binding process and from the ability to simulate it, given contemporary computational tools. In this review we present the challenges faced by binding free energy simulations within the context of lead optimization, survey the main tools currently in use for performing such calculations, and discuss their applications and performance based on selected examples. Our main conclusion is that despite great progress and numerous success cases, free energy simulations have yet to mature in order to become an integral component of the arsenal of tools available to practitioners in the field of lead optimization.