Covalent modifier drugs act by forming a chemical bond with their targets. This class of drugs includes kinase inhibitors such as ibrutinib, which has improved selectivity and affinity through the addition of its electrophilic acrylamide substituent to an active site cysteine thiol of its target. Modeling the activity of these drugs requires new computational methods to describe the mechanism of their reactions with their targets. We have developed an integrated workflow to model the deprotonation of the protein into the reactive thiolate state, the binding of the drug to the binding site using free energy perturbation, and QM/MM methods to calculate the kinetics and reaction energies of the covalent bond formation. We have applied these methods to model the binding of an acrylamide-containing covalent inhibitor of Bruton’s tyrosine kinase (BTK). Non-covalent interactions still account for the bulk of the binding energy, but the formation of the chemical bond results in a higher degree of affinity for kinases that possess a cysteine residue in the front pocket of the ATP binding site.

Modeling covalent modifiers of kinase proteins

2019 Fall National Meeting

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