Computational Investigations on Reaction Mechanisms of the Covalent Inhibitors Ponatinib and Analogs Targeting the Extracellular Signal-Regulated Kinases.

ABSTRACT: As an important cancer therapeutic target, extracellular signal-regulated kinases (ERK) are involved in triggering various cellular responses in tumors. Regulation of the ERK signaling pathway by the small molecular inhibitors is highly desired for the sake of cancer therapy. In contrast to the routine inhibitors targeting ERKs through long-range non-bonding interactions, Ponatinib, a covalent inhibitor to ERK2 with a macrocyclic structure characterized by the α,β-C=C unsaturated ketone, can form the stable -C(S)-C(H)-type complex via the four-center barrier due to the nucleophilic addition reaction of the thiol group of the Cys166 residue of ERK2 with the C=C double bond of Ponatinib with reaction free-energy barrier of 47.2 kcal/mol. Reaction mechanisms for the covalent binding were calc

SUBMITTER: Tian Y 

PROVIDER: S-EPMC10607051 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature