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- W2019585958 abstract "The fast and constant development of drug-resistant bacteria represents a serious medical emergence. To overcome this problem, the development of drugs with new structures and modes of action is urgently needed. In this context, avibactam represents a promising, innovative inhibitor of beta-lactamases with a novel molecular structure compared to previously developed inhibitors, showing a promising inhibitory activity toward a significant number of beta-lactamase enzymes. In this work, we studied, at the atomistic level, the mechanisms of formation of the covalent complex between avibactam and TEM-1, an experimentally well-characterized class A beta-lactamase, using classical and quantum mechanics/molecular mechanics (QM/MM) simulations combined with metadynamics. Our simulations provide a detailed structural and energetic picture of the molecular steps leading to the formation of the avibactam/TEM-1 covalent adduct. In particular, they support a mechanism in which the rate-determining step is the water-assisted Glu166 deprotonation by Ser70. In this mechanistic framework, the predicted activation energy is in good agreement with experimental kinetic measurements. Additionally, our simulations highlight the important role of Lys73 in assisting the Ser70 and Ser130 deprotonations. While based on the specific case of the avibactam/TEM-1, the simple protocol we present here can be immediately extended and applied to the study of covalent complex formation in different enzyme-inhibitor pairs." @default.
- W2019585958 created "2016-06-24" @default.
- W2019585958 creator A5013096980 @default.
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- W2019585958 date "2014-07-30" @default.
- W2019585958 modified "2023-10-14" @default.
- W2019585958 title "Inactivation of TEM-1 by Avibactam (NXL-104): Insights from Quantum Mechanics/Molecular Mechanics Metadynamics Simulations" @default.
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- W2019585958 doi "https://doi.org/10.1021/bi500589x" @default.
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