2. Academic Validation
  3. Design, synthesis, molecular docking and 3D-QSAR studies of potent inhibitors of enoyl-acyl carrier protein reductase as potential antimycobacterial agents

Design, synthesis, molecular docking and 3D-QSAR studies of potent inhibitors of enoyl-acyl carrier protein reductase as potential antimycobacterial agents

  • Eur J Med Chem. 2014 Jan:71:199-218. doi: 10.1016/j.ejmech.2013.11.004.
Uttam A More 1,  Shrinivas D Joshi 2,  Tejraj M Aminabhavi 3,  Andanappa K Gadad 4,  Mallikarjuna N Nadagouda 3,  Venkatrao H Kulkarni 3
Affiliations

Affiliations

  • 1 Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T's College of Pharmacy, Sangolli Rayanna Nagar, Dharwad 580 002, India; Centre for Research and Development, Prist University, Thanjavur 613 403, Tamil Nadu, India.
  • 2 Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T's College of Pharmacy, Sangolli Rayanna Nagar, Dharwad 580 002, India. Electronic address: shrinivasdj@rediffmail.com.
  • 3 Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T's College of Pharmacy, Sangolli Rayanna Nagar, Dharwad 580 002, India.
  • 4 School of Pharmacy, Faculty of Medical Sciences (The University of the West Indies, St. Augustine), Champs-Fleurs, Mount-Hope, Trinidad and Tobago.
PMID: 24292339 DOI: 10.1016/j.ejmech.2013.11.004
Abstract

In order to develop a lead antimycobacterium tuberculosis compound, a series of 52, novel pyrrole hydrazine derivatives have been synthesized and screened which target the essential enoyl-ACP reductase. The binding mode of the compounds at the active site of enoyl-ACP reductase was explored using surflex-docking method. The binding model suggests one or two hydrogen bonding interactions between pyrrole hydrazones and InhA Enzyme. Highly active compound 5r (MIC 0.2 μg/mL) showed hydrogen bonding interactions with Tyr158 and NAD(+) in the same manner as those of ligands PT70 and triclosan. The CoMFA and CoMSIA models generated with database alignment were the best in terms of overall statistics. The predictive ability of the CoMFA and CoMSIA models was determined using a test set of 13 compounds, which gave predictive correlation coefficients (r(pred)(2)) of 0.896 and 0.930, respectively.

Keywords

Anti-tubercular activity; CoMFA; CoMSIA; Enoyl-ACP reductase subunit A; Pyrrole hydrazones.

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