Mechanistic insight on the inhibition of D, D-carboxypeptidase from <i>Mycobacterium tuberculosis</i> by <i>β</i>-lactam antibiotics: an ONIOM acylation study

Ntombela, Thandokuhle; Seupersad, Anya; Maseko, Sibusiso B.; Ibeji, Collins U.; Tolufashe, Gideon F.; Maphumulo, Siyabonga I.; Naicker, Tricia; Baijnath, Sooraj; Maguire, Glenn E. M.; Govender, Thavendran; Lamichhane, Gyanu; Kruger, Hendrik G.

doi:10.1080/07391102.2021.1899052

Cited by 2 publications

(2 citation statements)

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“…Further, to make the theoretical model more realistic and to elucidate the acylation mechanism of DacB1 by β‐lactams Ntombela et al . performed ONIOM calculations using a 6‐membered ring transition state model as mentioned in Figure 3 [68] . The QM region comprised atoms of the serine residue, catalytic water molecule, and inhibitor.…”

Section: Enzyme Catalysis By Qm/mm Methodsmentioning

confidence: 99%

“…Further, to make the theoretical model more realistic and to elucidate the acylation mechanism of DacB1 by β-lactams Ntombela et al performed ONIOM calculations using a 6-membered ring transition state model as mentioned in Figure 3. [68] The QM region comprised atoms of the serine residue, catalytic water molecule, and inhibitor. The activation free energies were computed via single-point calculations on fully optimized structures using B3LYP/6-311þþ(d,p): AMBER and M06-2X/6-311þþ(d,p): AMBER with an electronic embedding scheme.…”

Section: Penicillin-binding Protein -D D-carboxypeptidasementioning

confidence: 99%

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QM/MM Studies on Enzyme Catalysis and Insight into Designing of New Inhibitors by ONIOM Approach: Recent Update

et al. 2023

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Computational enzymology is a rapidly developing area that uniquely provides deep insight into the fundamental processes of biological catalysis at the atomic level. Such in‐depth insight can ultimately be employed in designing potential inhibitors against the targets of interest. Computational enzymology covers a wide range of in‐silico approaches for investigating the enzyme‐catalyzed reaction mechanisms, among which combined quantum mechanics (QM) /molecular mechanics (MM) approaches have gained a lot of attention nowadays. This advanced approach generally involves a QM method (i. e. a method that estimates the electronic structure of the active site) and a simpler MM method (a method that includes the enzyme environment) to understand the enzymatic reactions. The QM/MM method has been widely tested in understanding the molecular mechanisms both at the structural and energetic levels and observed to best correlate with experimental studies of the enzymatic mechanism. It proposes a new mechanism that ultimately opens a new route for designing new potent, efficacious enzyme inhibitors. This review mainly covers wide applications of the ONIOM (Our own N‐layer Integrated molecular Orbital Molecular mechanics) method for decoding the enzymatic catalysis mechanism or designing potential small molecule inhibitors as treatment therapeutics in terms of free energy profiles. Moreover, this article also highlights employing QM/MM method in comprehending the mechanisms for drug metabolism and resistance (owing to mutations). This write‐up may encourage medicinal chemists and molecular biologists to explore this approach to propose more promising therapeutics to improve the quality of treatment.

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Section: Enzyme Catalysis By Qm/mm Methodsmentioning

confidence: 99%

Section: Penicillin-binding Protein -D D-carboxypeptidasementioning

confidence: 99%