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

Aim: Irreversible covalent drug inhibition is an emerging paradigm; however, critical gaps in unraveling the efficacy of molecular determinants still persist. Methodology: 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 [Delta G(bind)] = -40.4354 kcal/mol and reversible inhibition Delta G(bind) = -26.2515 kcal/mol); higher correlation in residual movement and multiple van der Waals interactions as evident from residue interaction analysis. Conclusion: 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. [GRAPHICS] .