Shama Khan1, Imane Bjij1,2, Robin M Betz3, Mahmoud Es Soliman1. 1. Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa. 2. Université Cadi Ayyad, Faculté des Sciences Semlalia, Département de Chimie, Av. My Abdellah, BP2390 Marrakech, Morocco. 3. Biophysics Program, Stanford University, Stanford, CA 94305, USA.
Abstract
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 [ΔGbind] = -40.4354 kcal/mol and reversible inhibition ΔGbind = -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.
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 [ΔGbind] = -40.4354 kcal/mol and reversible inhibition ΔGbind = -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.