The Driving Force for the Acylation of β ‐Lactam Antibiotics by L,D‐Transpeptidase 2: Quantum Mechanics/Molecular Mechanics (QM/MM) Study
| Autor: | Monsurat M. Lawal, Gyanu Lamichhane, Thavendran Govender, Hendrik G. Kruger, Glenn E. M. Maguire, Gideon F. Tolufashe, Collins U. Ibeji, Bahareh Honarparvar, Tricia Naicker |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Isodesmic reaction Molecular Structure Stereochemistry Bond strength Acylation beta-Lactams Atomic and Molecular Physics and Optics Transition state Anti-Bacterial Agents Ring strain QM/MM chemistry.chemical_compound Models Chemical chemistry Amide Peptidyl Transferases Lactam Quantum Theory Peptide bond Computer Simulation Physical and Theoretical Chemistry |
| Zdroj: | ChemPhysChem. 20:1126-1134 |
| ISSN: | 1439-7641 1439-4235 |
| DOI: | 10.1002/cphc.201900173 |
| Popis: | β-lactam antibiotics, which are used to treat infectious diseases, are currently the most widely used class of antibiotics. This study focused on the chemical reactivity of five- and six-membered ring systems attached to the β-lactam ring. The ring strain energy (RSE), force constant (FC) of amide (C-N), acylation transition states and second-order perturbation stabilization energies of 13 basic structural units of β-lactam derivatives were computed using the M06-2X and G3/B3LYP multistep method. In the ring strain calculations, an isodesmic reaction scheme was used to obtain the total energies. RSE is relatively greater in the five-(1a-2c) compared to the six-membered ring systems except for 4b, which gives a RSE that is comparable to five-membered ring lactams. These variations were also observed in the calculated inter-atomic amide bond distances (C-N), which is why the six-membered ring lactams C-N bond are more rigid than those with five-membered ring lactams. The calculated ΔG# values from the acylation reaction of the lactams (involving the S-H group of the cysteine active residue from L,D transpeptidase 2) revealed a faster rate of C-N cleavage in the five-membered ring lactams especially in the 1-2 derivatives (17.58 kcal mol-1 ). This observation is also reflected in the calculated amide bond force constant (1.26 mDyn/A) indicating a weaker bond strength, suggesting that electronic factors (electron delocalization) play more of a role on reactivity of the β-lactam ring, than ring strain. |
| Databáze: | OpenAIRE |
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