The Driving Force for the Acylation of ß-Lactam Antibiotics by L,D-Transpeptidase 2: Quantum Mechanics/Molecular Mechanics (QM/MM) Study.
Chemphyschem
; 20(9): 1126-1134, 2019 05 03.
Article
en En
| MEDLINE
| ID: mdl-30969480
ABSTRACT
ß-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 ß-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 ß-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 (17.58â
kcal mol-1 ). This observation is also reflected in the calculated amide bond force constant (1.26â
mDyn/A) indicating a weaker bond strength, suggesting that electronic factors (electron delocalization) play more of a role on reactivity of the ß-lactam ring, than ring strain.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Peptidil Transferasas
/
Beta-Lactamas
/
Antibacterianos
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Chemphyschem
Asunto de la revista:
BIOFISICA
/
QUIMICA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Sudáfrica