Discovery of novel InhA reductase inhibitors: application of pharmacophore- and shape-based screening approach
| Autor: | Lluis Ballell, Daniel Alvarez-Gomez, Siddharth Malik, Uday Chandra Kumar, Prashanta Kumar-Sahu, Sarma Jarp, Dharmarajan Sriram, S. K. Mahmood, Suneel Kumar Bvs, Sridevi Pulakanam |
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| Rok vydání: | 2013 |
| Předmět: |
Pharmacology
medicine.drug_class INHA Antitubercular Agents Mycobacterium tuberculosis Reductase Biology Antimycobacterial biology.organism_classification Molecular Docking Simulation Combinatorial chemistry Bacterial Proteins Drug development Docking (molecular) Drug Design Drug Discovery medicine Humans Tuberculosis Molecular Medicine Enzyme Inhibitors Pharmacophore Oxidoreductases |
| Zdroj: | Future Medicinal Chemistry. 5:249-259 |
| ISSN: | 1756-8927 1756-8919 |
| DOI: | 10.4155/fmc.12.211 |
| Popis: | 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. Conclusion: Further optimization of these analogues is in progress and will update in due course. |
| Databáze: | OpenAIRE |
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