Covalent Inhibitors have been emerging as a very important drug class in recent years, largely owning to their many unique advantages as compared to noncovalent inhibitors, including, longer duration of action, lower prolonged systemic exposure, higher potency and selectivity etc. However, the potential off-target toxicity of covalent inhibitors, particularly of irreversible covalent inhibitors, represents a great challenge in covalent drug development. Therefore, accurate calculation of protein covalent inhibitor reaction kinetics to guide the design of selective inhibitors is very important in covalent drug development. In the present paper, we present a computational method to calculate the relative reaction kinetics Delta_log(kinact/Ki) between irreversible covalent inhibitors and their protein receptors. The method combines quantum mechanics calculations of the transition state barrier height for the reaction between the warhead of the inhibitor and a single protein residue, and molecular mechanics based free energy calculations to account for the effect of protein environment in the binding site on the transition state barrier. The method was tested on 4 pharmaceutically interesting irreversible covalent binding systems involving 28 ligands; the MUE of Delta_log(kinact/Ki) between the predictions and experimental results for these tested systems is 0.43. This is to our knowledge the first time where the reaction kinetics of protein irreversible covalent inhibition has been directly calculated with physics-based free energy calculation methods and transition state theory. We anticipate the outstanding accuracy demonstrated here across a broad range of target classes may help the design of selective covalent inhibitors.

Accurate and reliable prediction of irreversible covalent inhibitor binding kinetics

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.