Reversible versus irreversible inhibition modes of ERK2: a comparative analysis for ERK2 protein kinase in cancer therapy

Irreversible covalent drug inhibition is an emerging paradigm; however, critical gaps in unraveling the efficacy of molecular determinants still persist.

We compare two ERK2 inhibitors with different binding modes. A 5-7-Oxozeaenol is selective inhibitor which irreversibly binds ERK2 by the formation of covalent bond with Cys166 while 5-iodotubercidin binds noncovalently. Result & discussion: Covalent inhibition showed greater protein stability, favorable binding energetics (irreversible inhibition binding free energy [ΔG_bind] = -40.4354 kcal/mol and reversible inhibition ΔG_bind = -26.2515 kcal/mol); higher correlation in residual movement and multiple van der Waals interactions as evident from residue interaction analysis.

This investigation of the different inhibition modes of ERK2 would assist toward the design of more potent and highly site-specific covalent inhibitors in cancer therapy.