title: 3D-QSAR studies and shape based virtual screening for identification of novel hits to inhibit MbtA in Mycobacterium tuberculosis.
abstract: Mycobacterium tuberculosis, the pathogen responsible for tuberculosis, uses various strategies to survive in a variety of host lesions. The re-emergence of multi-drug-resistant strains of M. tuberculosis underlines the necessity to discover new molecules. Inhibitors of aryl acid adenylating enzyme, MbtA, involved in siderophore biosynthesis in M. tuberculosis, are being explored as potential anti tubercular agents. In this study, we have used 3D-QSAR models and shape based virtual screening to identify novel MbtA inhibitors. 3D-QSAR studies were carried out on nucleoside bisubstrate derivatives. Both Comparative Molecular Field Analysis (r(2) = .944 and r(2)(pred) = .938) and Comparative Molecular Similarity Indices Analysis (r(2) = .892 and r(2)(pred) = .842) models, developed using Gasteiger charges with all fields, predicted efficiently. A total of 13 hits were identified as novel prospective inhibitors for MbtA by utilizing an insilico workflow. Out of 13 hits, five top ranked hits were used for further molecular dynamics studies to gain more insights about the stability of the complexes.
authors.affiliation: a 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.forename: Nanda
authors.initials: N
authors.lastname: Ghoshal
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry*; D020134:Catalytic Domain; D015195:Drug Design; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008025:Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D008025:Ligases; C526815:salicyl-AMP ligase, Mycobacterium tuberculosis
keywords: 3D-QSAR; MD simulation; docking; shape based virtual screening; tuberculosis