Targeting the cell wall ofMycobacterium tuberculosis: a molecular modeling investigation of the interaction of imipenem and meropenem withL,D-transpeptidase 2

Abstract

The single crystal X-ray structure of the extracellular portion of the L,D-transpeptidase (ex-LdtMt2 - residues 120-408) enzyme was recently reported. It was observed that imipenem and meropenem inhibit activity of this enzyme, responsible for generating L,D-transpeptide linkages in the peptidoglycan layer of Mycobacterium tuberculosis. Imipenem is more active and isothermal titration calorimetry experiments revealed that meropenem is subjected to an entropy penalty upon binding to the enzyme. Herein, we report a molecular modeling approach to obtain a molecular view of the inhibitor/enzyme interactions. The average binding free energies for nine commercially available inhibitors were calculated using MM/GBSA and Solvation Interaction Energy (SIE) approaches and the calculated energies corresponded well with the available experimentally observed results. The method reproduces the same order of binding energies as experimentally observed for imipenem and meropenem. We have also demonstrated that SIE is a reasonably accurate and cost-effective free energy method, which can be used to predict carbapenem affinities for this enzyme. A theoretical explanation was offered for the experimental entropy penalty observed for meropenem, creating optimism that this computational model can serve as a potential computational model for other researchers in the field.

Non-classical transpeptidases yield insight into new antibacterials

“…Subsequent to these events, or earlier, precedented retro-aldol reaction can ensue to expel the hydroxyethyl side chain as acetaldehyde 3 , 26 . While these proposals are in agreement with a mechanism of carbapenem-induced inhibition of Ldt Mt2 derived from a theoretical free energy study 27 , our data provide direct evidence of additional cleavage and rearrangement mechanisms beyond the loss of the C6 hydroxymethyl group thought to be common to carbapenems 14 . This information expands design options for carbapenems having alternative modes of transpeptidase inactivation.…”

Molecular insight on the non-covalent interactions between carbapenems and l,d-transpeptidase 2 from Mycobacterium tuberculosis: ONIOM study

“…During geometry optimization it was observed that the carbapenems experienced slight movement inside the binding site of LdtMt2 (Figure 2) as expected 22 . The short-range distances between the sulfur atom of the catalytic cysteine residue and the carbonyl carbon of the βlactam ring of the carbapenem were in the range of 3.6 Å to 3.9 Å.…”

“…Besides several publications in the field of computer-aided drug discovery for the potential anti-HIV agents made by our research group [19][20][21] , the theoretical binding free energies of the commercially available inhibitors against LdtMt2 were also reported using MM-GBSA and solvation interaction energy (SIE) methods 22 . The role of LdtMt2 flap opening and closing upon complexation of the substrate and three carbapenems, namely: ertapenem, imipenem and meropenem, was also reported using 140 ns molecular dynamics simulation with explicit water solvent 23 .…”

Competition Between Phenothiazines and BH3 Peptide for the Binding Site of the Antiapoptotic BCL-2 Protein

“…Finally, SIE (Solvated Interaction Energy) methodology was employed to estimate the binding free energy related to the ligand-receptor complex by applying the boundary element method (BEM) to solve the Poisson-Boltzmann equation. This method also uses implicit solvation in the study of protein-ligand complexes (Naïm et al, 2007;Silva et al, 2016). For this, SIE was used in this study to estimate the binding free energy between BCL-2 and the five phenothiazine derivatives, or the BH3 peptide, from the most stable subtrajectories generated by the MD simulations.…”