Prediction of drug candidates' sensitivity toward autoxidation: computational estimation of C-H dissociation energies of carbon-centered radicals.

A method to predict a compound's sensitivity toward autoxidation using bond dissociation energies for hydrogen abstraction is described. The methodology is based on quantum mechanics and has been validated with a small molecule test set. Through this work, it has been observed that stabilization of an incipient radical by more than a single functional group is normally required to trigger autoxidation. The method has also been used to understand salt effects, wherein protonation of a basic amine stabilizes proximal C-H bonds to autoxidation. It can be used to support understanding of autoxidation processes and can form a predictive role for propensity to form potentially genotoxic and other degradation products. An automated protocol has been developed that allows the nonspecialist to perform quantum chemical calculations. The protocol is robust to enable general usage such that drug-like molecules can be handled by the tool and give an answer in hours (up to some days) depending on the size of the molecule. The efficiency of the tool makes it possible to perform risk assessment for autoxidation of small lists of molecules and could typically be used for shortlisted candidates before drug nomination, during drug formulation development, and during due diligence for in-licensing compounds.