title: Identification of hotspot regions of MurB oxidoreductase enzyme using homology modeling, molecular dynamics and molecular docking techniques.
abstract: Despite the availability of effective chemotherapy and a moderately protective vaccine, new anti-tuberculosis agents are urgently needed to decrease the global incidence of tuberculosis (TB) disease. The MurB gene belongs to the bacterial cell wall biosynthesis pathway and is an essential drug target in Mycobacterium tuberculosis (Mtb) that has no mammalian counterparts. Here, we present an integrated approach involving homology modeling, molecular dynamics and molecular docking studies on Mtb-MurB oxidoreductase enzyme. A homology model of Mtb-MurB enzyme was built for the first time in order to carry out structure-based inhibitor design. The accuracy of the model was validated using different techniques. The molecular docking study on this enzyme was undertaken using different classes of well known MurB inhibitors. Estimation of binding free energy by docking analysis indicated the importance of Tyr155, Arg156, Ser237, Asn241 and His304 residues within the Mtb-MurB binding pocket. Our computational analysis is in good agreement with experimental results of site-directed mutagenesis. The present study should therefore play a guiding role in the experimental design of Mtb-MurB inhibitors for in vitro/in vivo analysis.
authors.affiliation: Centre for Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, SAS Nagar, 160 062 Punjab, India.
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Saravanan
authors.forename: Akanksha
authors.initials: A
authors.lastname: Arvind
authors.forename: C Gopi
authors.initials: CG
authors.lastname: Mohan
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002237:Carbohydrate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli; D006801:Humans; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000201:enzymology / Q000235:genetics; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D013211:Staphylococcus aureus; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000596:Amino Acids; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D014537:Uridine Diphosphate N-Acetylglucosamine; C038277:UDP-N-acetylglucosamine-enolpyruvate; D002237:Carbohydrate Dehydrogenases; C023215:UDP-N-acetylmuramate dehydrogenase