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Multiscale calculations reveal new insights into the reaction mechanism between KRAS^G12C and α, β-unsaturated carbonyl of covalent inhibitors.

ABSTRACT: Utilizing α,β-unsaturated carbonyl group as Michael acceptors to react with thiols represents a successful strategy for developing KRAS^G12C inhibitors. Despite this, the precise reaction mechanism between KRAS^G12C and covalent inhibitors remains a subject of debate, primarily due to the absence of an appropriate residue capable of deprotonating the cysteine thiol as a base. To uncover this reaction mechanism, we first discussed the chemical reaction mechanism in solvent conditions via density functional theory (DFT) calculation. Based on this, we then proposed and validated the enzymatic reaction mechanism by employing quantum mechanics/molecular mechanics (QM/MM) calculation. Our QM/MM analysis suggests that, in biological conditions, proton transfer and nucleophilic

SUBMITTER: Yan X

PROVIDER: S-EPMC11015740 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature

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Multiscale calculations reveal new insights into the reaction mechanism between KRAS^G12C and α, β-unsaturated carbonyl of covalent inhibitors.

OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Multiscale calculations reveal new insights into the reaction mechanism between KRASG12C and α, β-unsaturated carbonyl of covalent inhibitors.

OmicsDI is part of the ELIXIR infrastructure

Tweets

Multiscale calculations reveal new insights into the reaction mechanism between KRAS^G12C and α, β-unsaturated carbonyl of covalent inhibitors.