Our experiments have revealed significant differences in susceptibility to covalent inhibition between tyrosine phosphatases, as well as more granular effects of ligand structure on potency and selectivity. We sought to identify divergent structural features of these enzymes that might explain their differences in covalent inhibition. We first used covalent docking to predict plausible binding poses for a few select compounds against four phosphatases: PTP1B, HePTP, SHP1, and SHP2 (Figure ). Based on these models, we identified residues that made direct contact with the molecules and examined conservation across the panel of phosphatases used in this study. Most first-shell residues were conserved, ruling out these residues as differentiating factors in our analysis (Figure ).