Can Relative Binding Free Energy Predict Selectivity of Reversible Covalent Inhibitors?

ABSTRACT: Reversible covalent inhibitors have many clinical advantages over noncovalent or irreversible covalent drugs. However, apart from selecting a warhead, substantial efforts in design and synthesis are needed to optimize noncovalent interactions to improve target-selective binding. Computational prediction of binding affinity for reversible covalent inhibitors presents a unique challenge since the binding process consists of multiple steps, which are not necessarily independent of each other. In this study, we lay out the relation between relative binding free energy and the overall reversible covalent binding affinity using a two-state binding model. To prove the concept, we employed free energy perturbation (FEP) coupled with λ-exchange molecular dynamics method to calculate the binding fre

SUBMITTER: Chatterjee P 

PROVIDER: S-EPMC5729052 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature