Ranking Reversible Covalent Drugs: From Free Energy Perturbation to Fragment Docking

Reversible covalent inhibitors have drawn increasing attention in drug design, as they are likely more potent than noncovalent inhibitors and less toxic than covalent inhibitors. Despite those advantages, the computational prediction of reversible covalent binding presents a formidable challenge because the binding process consists of multiple steps and quantum mechanics (QM) level calculation is needed to estimate the covalent binding free energy. It has been shown that the dissociation rates and the equilibrium dissociation constants vary significantly even with similar warheads, due to noncovalent interactions. We have previously used a simplistic two-state model for predicting the relative binding selectivity of reversible covalent inhibitors ( J. Am. Chem. Soc. 2017, 139, 17945). Here we go beyond binding selectivity and demonstrate that it is possible to use free energy perturbation (FEP) molecular dynamics (MD) to calculate the overall reversible covalent binding using a specially designed thermody...