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Theoretical insights on the inhibition mechanism of a class A Serine Hydrolase by avibactam
Author(s) -
Lizana Ignacio,
Delgado Eduardo J.
Publication year - 2018
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.25340
Subject(s) - chemistry , serine , nucleophile , active site , stereochemistry , residue (chemistry) , molecular mechanics , protonation , qm/mm , concerted reaction , hydrolase , reaction mechanism , molecular dynamics , enzyme , computational chemistry , biochemistry , catalysis , organic chemistry , ion
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.