Normalizing Covalent Potency for Electrophilicity with Ligand Reactivity Efficiency

Covalent modalities represent an important component of the modern medicinal chemist's toolbox for pursuing challenging targets in drug discovery. By taking a "covalent-first" approach to identifying druggable pockets on challenging-to-drug targets, we and others have expanded accessible target space and driven fragment-like hits to clinical-stage molecules. The field has long recognized intrinsic warhead reactivity as a key parameter to monitor, typically addressed by determining k_inact and K_I values, which are impractically time-intensive and can be misleading regarding reactivity. Here we present an alternative way to normalize potency for electrophilicity utilizing glutathione (GSH) consumption data, which enables us to extract target-specific improvements in potency, a metric we term ligand reactivity efficiency (LRE). Our hope is that the details of our approach and this metric will simplify the rational design of covalent drugs for fellow practitioners in the field.