title: A comparative modeling and molecular docking study on Mycobacterium tuberculosis targets involved in peptidoglycan biosynthesis.
abstract: An alarming rise of multidrug-resistant Mycobacterium tuberculosis strains and the continuous high global morbidity of tuberculosis have reinvigorated the need to identify novel targets to combat the disease. The enzymes that catalyze the biosynthesis of peptidoglycan in M. tuberculosis are essential and noteworthy therapeutic targets. In this study, the biochemical function and homology modeling of MurI, MurG, MraY, DapE, DapA, Alr, and Ddl enzymes of the CDC1551 M. tuberculosis strain involved in the biosynthesis of peptidoglycan cell wall are reported. Generation of the 3D structures was achieved with Modeller 9.13. To assess the structural quality of the obtained homology modeled targets, the models were validated using PROCHECK, PDBsum, QMEAN, and ERRAT scores. Molecular dynamics simulations were performed to calculate root mean square deviation (RMSD) and radius of gyration (Rg) of MurI and MurG target proteins and their corresponding templates. For further model validation, RMSD and Rg for selected targets/templates were investigated to compare the close proximity of their dynamic behavior in terms of protein stability and average distances. To identify the potential binding mode required for molecular docking, binding site information of all modeled targets was obtained using two prediction algorithms. A docking study was performed for MurI to determine the potential mode of interaction between the inhibitor and the active site residues. This study presents the first accounts of the 3D structural information for the selected M. tuberculosis targets involved in peptidoglycan biosynthesis.
authors.affiliation: a Catalysis and Peptide Research Unit, School of Health Sciences , University of KwaZulu-Natal , Durban 4001 , South Africa.
authors.forename: Zeynab
authors.initials: Z
authors.lastname: Fakhar
authors.affiliation: a Catalysis and Peptide Research Unit, School of Health Sciences , University of KwaZulu-Natal , Durban 4001 , South Africa.
authors.forename: Suhashni
authors.initials: S
authors.lastname: Naiker
authors.affiliation: b Laboratório de Planejamento de Fármacos, Instituto de Ciências Exatas e Naturais , Instituto de Ciências Biológicas, Universidade Federal do Pará , CEP 66075-110, Belém , Pará , Brazil.
authors.forename: Claudio N
authors.initials: CN
authors.lastname: Alves
authors.affiliation: a 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: a Catalysis and Peptide Research Unit, School of Health Sciences , University of KwaZulu-Natal , Durban 4001 , South Africa.|c School of Chemistry and Physics , University of KwaZulu-Natal , 4001 Durban , South Africa.
authors.forename: Glenn E M
authors.initials: GE
authors.lastname: Maguire
authors.affiliation: b Laboratório de Planejamento de Fármacos, Instituto de Ciências Exatas e Naturais , Instituto de Ciências Biológicas, Universidade Federal do Pará , CEP 66075-110, Belém , Pará , Brazil.
authors.forename: Jeronimo
authors.initials: J
authors.lastname: Lameira
authors.affiliation: d Division of Infectious Diseases, Center for Tuberculosis Research , Johns Hopkins University School of Medicine , Baltimore , MD 21205 , USA.
authors.forename: Gyanu
authors.initials: G
authors.lastname: Lamichhane
authors.affiliation: a Catalysis and Peptide Research Unit, School of Health Sciences , University of KwaZulu-Natal , Durban 4001 , South Africa.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Kruger
authors.affiliation: a Catalysis and Peptide Research Unit, School of Health Sciences , University of KwaZulu-Natal , Durban 4001 , South Africa.
authors.forename: Bahareh
authors.initials: B
authors.lastname: Honarparvar
mesh_terms: D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004798:Enzymes / Q000737:chemistry*; D008024:Ligands; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D010457:Peptidoglycan / Q000096:biosynthesis; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D004798:Enzymes; D008024:Ligands; D010457:Peptidoglycan
keywords: Mycobacterium tuberculosis; homology modeling; molecular docking; molecular dynamics simulation; peptidoglycan; radius of gyration (Rg); root mean square deviation (RMSD)