title: Homology modeling, molecular dynamics and inhibitor binding study on MurD ligase of Mycobacterium tuberculosis.
abstract: The cell wall of mycobacterium offers well validated targets which can be exploited for discovery of new lead compounds. MurC-MurF ligases catalyze a series of irreversible steps in the biosynthesis of peptidoglycan precursor, i.e. MurD catalyzes the ligation of D-glutamate to the nucleotide precursor UMA. The three dimensional structure of Mtb-MurD is not known and was predicted by us for the first time using comparative homology modeling technique. The accuracy and stability of the predicted Mtb-MurD structure was validated using Procheck and molecular dynamics simulation. Key interactions in Mtb-MurD were studied using docking analysis of available transition state inhibitors of E.coli-MurD. The docking analysis revealed that analogues of both L and D forms of glutamic acid have similar interaction profiles with Mtb-MurD. Further, residues His192, Arg382, Ser463, and Tyr470 are proposed to be important for inhibitor-(Mtb-MurD) interactions. We also identified few pharmacophoric features essential for Mtb-MurD ligase inhibitory activity and which can further been utilized for the discovery of putative antitubercular chemotherapy.
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, 160062, India.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Arvind
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Saravanan
authors.forename: C Gopi
authors.initials: CG
authors.lastname: Mohan
mesh_terms: D000595:Amino Acid Sequence; D018698:Glutamic Acid / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D018698:Glutamic Acid; D010453:Peptide Synthases; C053379:UDP-N-acetylmuramoylalanine-D-glutamate ligase