Inhibitory small-molecule drugs that form covalent bonds with their targets, i.e. covalent inhibitors, have historically received less attention than noncovalent inhibitors. Despite their potential for longer on-target residency time and selectivity, covalent inhibitors may also lead to higher cytotoxicity through off-target covalent interactions. Capitalizing on this potential in the clinical setting therefore requires proper design and optimization of drug compounds, which is limited by a lackluster understanding of their fundamental dynamics. Specifically, the medicinal implications and mechanistic determinants of conformational relationships between the linked (when the inhibitor is covalently bound to the protein) and unlinked states have not yet been resolved. To address this issue, we compared experimental measurements of potency to atomistic molecular dynamics (MD) simulations of a diverse set of systems comprising competitive covalent inhibitors and kinases. Due to the popularity and medicinal importance of kinase inhibition, the initial coordinates of these simulations were derived from published structures of covalently inhibited kinases. During preliminary analysis, we find that reported pIC50’s and residence times were proportional to the overlap of linked and unlinked conformations. This relationship was observed in groups of cysteine- and lysine-targeted inhibitors, suggesting that conformational comparisons between the linked and unlinked states could be useful for a broad range of covalent inhibitors. Recent results will be presented on how conformational substates may be used to guide covalent inhibitor design.

Predicting the potency of covalent kinase inhibitors from computations

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