Theoretical insights on the inhibition mechanism of a class A Serine Hydrolase by avibactam
© 2018 Wiley Periodicals, Inc.
| Publié dans: | Journal of computational chemistry. - 1984. - 39(2018), 24 vom: 15. Sept., Seite 1943-1948 |
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| Auteur principal: | |
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| Format: | Article en ligne |
| Langue: | English |
| Publié: |
2018
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| Accès à la collection: | Journal of computational chemistry |
| Sujets: | Journal Article Research Support, Non-U.S. Gov't CTX-M-15 MD simulation QM/MM avibactam Azabicyclo Compounds beta-Lactamase Inhibitors 7352665165 beta-lactamase CTX-M-15 plus... |
| Résumé: | © 2018 Wiley Periodicals, Inc. The inhibition mechanism of CTX-M-15 class A serine hydrolase by the inhibitor avibactam is addressed by a combined molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) approach postulating that the residue Ser70 is the sole reacting residue, that is, itself may play the role of the acid-base species required for the enzyme inhibition. Other residues located in the active site have key participation in the positioning of the inhibitor in the right conformation to favor the attack of Ser70, in addition to the stabilization of the transition state by electrostatic interactions with avibactam. The results validate the hypothesis and show that the reaction follows an asynchronous concerted mechanism, in which the nucleophilic attack of the hydroxyl oxygen of Ser70 precedes the protonation of the amidic nitrogen and ring opening. The calculated activation barrier is 16 kcal/mol in agreement with the experimental evidence. © 2018 Wiley Periodicals, Inc |
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| Description: | Date Completed 18.09.2019 Date Revised 18.09.2019 published: Print-Electronic Citation Status MEDLINE |
| ISSN: | 1096-987X |
| DOI: | 10.1002/jcc.25340 |