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

Abstract 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 ω B97X 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 −1 respectively. 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.