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

Journal of Biomolecular Structure & Dynamics
José Rogério A SilvaCláudio Nahum Alves

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, cr...Continue Reading

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Citations

May 20, 2016·The Journal of Physical Chemistry. B·Nicholus BhattacharjeeCatherine M Bougault
Jul 16, 2016·Journal of Biomolecular Structure & Dynamics·Alessia RuggieroRita Berisio
Nov 8, 2016·Nature Chemical Biology·Pankaj KumarGyanu Lamichhane
Nov 15, 2017·Journal of Biomolecular Structure & Dynamics·Michell O AlmeidaKathia M Honorio
Apr 21, 2020·Frontiers in Chemistry·Aline Lagoeiro do CarmoKathia Maria Honorio
May 31, 2018·Journal of Computer-aided Molecular Design·Thandokuhle NtombelaBahareh Honarparvar

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Methods Mentioned

BETA
X-ray
isothermal titration calorimetry

Software Mentioned

GAFF
Surflex
. py
GAUSSIAN09
Molegro Virtual Docker ( MVD )
SIETRAJ
MolDock
MMPBSA
AMBER
MVD

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