title: Integration of ligand and structure based approaches for identification of novel MbtI inhibitors in Mycobacterium tuberculosis and molecular dynamics simulation studies.
abstract: Mycobacterium tuberculosis is an obligate pathogen of mammals and is responsible for more than two million deaths annually. The ability to acquire iron from the extracellular environment is a key determinant of pathogenicity in mycobacteria. M. tuberculosis acquires iron exclusively through the siderophores. Several lines of evidence suggest that siderophores have a critical role in bacterial growth and virulence. Hence, in the present study, we have used a combined ligand and structure-based drug design approach for identification of novel inhibitors against salicylate synthase MbtI, a unique and essential enzyme for the biosynthesis of siderophores in M. tuberculosis. We have generated the ligand based and structure based pharmacophores and validated exhaustively. From the validation results it was found that GH (Goodness of Hit) scores for the selected ligand based and structure based pharmacophore models were 0.89 and 0.97, respectively, which indicate that the quality of the pharmacophore models are acceptable as GH value is >0.7. The validated pharmacophores were used for screening the ZINC database. A total of 73 hits, obtained through various insilico screening techniques, were further enriched to 17 hits using docking studies. Molecular dynamics simulations were carried out to compare the binding mode and stability of complexes of MbtI bound with substrate, known inhibitors, and three top ranked hits. The results obtained in this study gave assurance about the identified hits as prospective inhibitors of MbtI.
authors.affiliation: Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Maganti
authors.affiliation: National Institute of Pharmaceutical Education and Research(NIPER), 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Grandhi
authors.affiliation: Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India. Electronic address: nghoshal@iicb.res.in.
authors.forename: Nanda
authors.initials: N
authors.lastname: Ghoshal
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020134:Catalytic Domain; D002827:Chorismic Acid / Q000737:chemistry / Q000378:metabolism; D030562:Databases, Protein; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D025341:Principal Component Analysis; D015203:Reproducibility of Results; D020156:Salicylic Acid / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D008024:Ligands; D002827:Chorismic Acid; D020156:Salicylic Acid
keywords: MbtI; Molecular Dynamics; Pharmacophore; Tuberculosis; Virtual Screening