title: Targeting the cell wall of Mycobacterium tuberculosis: a molecular modeling investigation of the interaction of imipenem and meropenem with L,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.
authors.affiliation: a Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais , Universidade Federal do Pará , CP 11101, Belém , PA 66075-110 , Brazil.
authors.forename: José Rogério A
authors.initials: JR
authors.lastname: Silva
authors.affiliation: b Department of Medicine, Division of Infectious Diseases , Johns Hopkins University School of Medicine , Baltimore , MD 21205 , USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
authors.affiliation: c Catalysis and Peptide Research Unit, School of Health Sciences , University of KwaZulu-Natal , Durban 4001 , South Africa.
authors.forename: Thavendran
authors.initials: T
authors.lastname: Govender
authors.affiliation: c Catalysis and Peptide Research Unit, School of Health Sciences , University of KwaZulu-Natal , Durban 4001 , South Africa.
authors.forename: Gyanu
authors.initials: G
authors.lastname: Lamichhane
authors.affiliation: d Taskforce to study Resistance Emergence & Antimicrobial Development Technology , Johns Hopkins University School of Medicine , Baltimore , MD 21205 , USA.
authors.forename: Glenn E M
authors.initials: GE
authors.lastname: Maguire
authors.affiliation: d Taskforce to study Resistance Emergence & Antimicrobial Development Technology , Johns Hopkins University School of Medicine , Baltimore , MD 21205 , USA.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Kruger
authors.affiliation: a Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais , Universidade Federal do Pará , CP 11101, Belém , PA 66075-110 , Brazil.
authors.forename: Jeronimo
authors.initials: J
authors.lastname: Lameira
authors.affiliation: a Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais , Universidade Federal do Pará , CP 11101, Belém , PA 66075-110 , Brazil.
authors.forename: Cláudio N
authors.initials: CN
authors.lastname: Alves
mesh_terms: D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism*; D015378:Imipenem / Q000737:chemistry / Q000494:pharmacology*; D000077731:Meropenem; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D010458:Peptidyl Transferases / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D013816:Thermodynamics; D013845:Thienamycins / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D013845:Thienamycins; D015378:Imipenem; D010458:Peptidyl Transferases; D000077731:Meropenem
keywords: GBSA; L,D-transpeptidase; Mycobacterium tuberculosis; SIE; binding free energy; carbapenems; molecular dynamics