title: Discovery of novel InhA reductase inhibitors: application of pharmacophore- and shape-based screening approach.
abstract: BACKGROUND
  InhA is a promising and attractive target in antimycobacterial drug development. InhA is involved in the reduction of long-chain trans-2-enoyl-ACP in the type II fatty acid biosynthesis pathway of Mycobacterium tuberculosis. Recent studies have demonstrated that InhA is one of the targets for the second line antitubercular drug ethionamide.
  
  
  RESULTS
  In the current study, we have generated quantitative pharmacophore models using known InhA inhibitors and validated using a large test set. The validated pharmacophore model was used as a query to screen an in-house database of 400,000 compounds and retrieved 25,000 hits. These hits were further ranked based on its shape and feature similarity with potent InhA inhibitor using rapid overlay of chemical structures (OpenEye™) and subsequent hits were subjected for docking. Based on the pharmacophore, rapid overlay of chemical structures model and docking interactions, 32 compounds with more than eight chemotypes were selected, purchased and assayed for InhA inhibitory activity. Out of the 32 compounds, 28 demonstrated 10-38% inhibition against InhA at 10 µM.
  
  
  CONCLUSIONS
  Further optimization of these analogues is in progress and will update in due course.
authors: GVK Biosciences Pvt. Ltd, Plot no: 79, Nacharam, IDA-Mallapur, Hyderabad 500076, Andhra Pradesh, India.
authors: Uday Chandra
authors: UC
authors: Kumar
authors: Suneel Kumar
authors: SK
authors: Bvs
authors: Shaik
authors: S
authors: Mahmood
authors: Sriram
authors: S
authors: D
authors: Prashanta
authors: P
authors: Kumar-Sahu
authors: Sridevi
authors: S
authors: Pulakanam
authors: Lluís
authors: L
authors: Ballell
authors: Daniel
authors: D
authors: Alvarez-Gomez
authors: Siddharth
authors: S
authors: Malik
authors: Sarma
authors: S
authors: Jarp
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium