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) by β-lactam derivatives. Ldt 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 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 by the selected β-lactams were obtained as 13.67, 20.90, 22.88, 24.29, 27.86 and 28.26 kcal molrespectively. 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. This model provides further validation of the catalytic inhibition mechanism of LDTs with atomistic detail.