Protein-ligand binding free energy and kinetics

Predicting drug efficacy with computational tools remains one of the major challenges in drug discovery. Drug efficacy depends on the affinity of a small molecule for its biological counterpart. In addition, it has recently been reported that drug efficacy can also be related to the time that a small molecule spends in contact with its biological target (i.e. the kinetics of unbinding, koff).1 From a computational standpoint, several approaches to the free energy estimation have been reported, while only a few examples have appeared in the literature aimed at predicting the koff of binary complexes. Recently, we used steered molecular dynamics (SMD) to pull a series of inhibitors out of their complexes with a target enzyme.2 In particular, we investigated a series of flavonoid derivatives, and we computed the force that was required to extract inhibitors from complexes with the FabZ enzyme, a promising anti-malarial target. Although we were not able to determine the flavonoids-FabZ binding free energy, we could clearly distinguish active from inactive inhibitors, by estimating the kinetics stability of these complexes. This was accomplished by calculating the forces required for pulling each ligand out of the protein embrace.3 In a subsequent study, we investigated the full unbinding pathway of a potent and selective COX-2 inhibitor, showing that the binding kinetics can play a role in COX-2 inhibition efficacy and selectivity.4 References [1] Copeland, R.A., Pompliano, D.R. and Meek, T.D. Nat. Rev. Drug Discov. 2006, 5, 21-42. [2] Colizzi, F., Perozzo, R., Scapozza, L., Recanatini, M. and Cavalli, A. J. Am. Chem. Soc. 2010, 132, 7361-7371. [3] Jorgensen, W.L. Nature 2010, 466, 42-43. [4] Limongelli, V., Bonomi, M., Marinelli, L., Gervasio, F.L., Cavalli, A., Novellino, E., Parrinello, M. Proc. Natl. Acad. Sci. USA 2010, 107, 5411-6