Inhibition mechanism of L,D-transpeptidase 5 in presence of the β-lactams using ONIOM method

Tuberculosis (TB) is one of the world's deadliest diseases resulting from infection by the bacterium, Mycobacterium tuberculosis (M.tb). The L,D-transpeptidase enzymes catalyze the synthesis of 3 → 3 transpeptide linkages which are predominant in the peptidoglycan of the M.tb cell wall. Carbapenems is class of β-lactams that inactivate L,D-transpeptidases by acylation, although differences in antibiotic side chains modulate drug binding and acylation rates. Herein, we used a two-layered our Own N-layer integrated Molecular Mechanics ONIOM method to investigate the catalytic mechanism of L,D-transpeptidase 5 (Ldt_Mt5) by β-lactam derivatives. Ldt_Mt5 complexes with six β-lactams, ZINC03788344 (1), ZINC02462884 (2), ZINC03791246 (3), ZINC03808351 (4), ZINC03784242 (5) and ZINC02475683 (6) were simulated. The QM region (high-level) comprises the β-lactam, one water molecule and the Cys360 catalytic residue, while the rest of the Ldt_Mt5 residues were treated with AMBER force field. The activation energies (ΔG^#) were calculated with B3LYP, M06-2X and ωB97X density functionals with 6–311++G(2d, 2p) basis set. The ΔG^# for the acylation of Ldt_Mt5 by the selected β-lactams were obtained as 13.67, 20.90, 22.88, 24.29, 27.86 and 28.26 kcal mol⁻¹respectively. Several of the compounds showed an improved ΔG^# when compared to the previously calculated energies for imipenem and meropenem for the acylation step for Ldt_Mt5. This model provides further validation of the catalytic inhibition mechanism of LDTs with atomistic detail.