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Discovery of newer pyrazole derivatives with potential anti-tubercular activity via 3D-QSAR based pharmacophore modelling, virtual screening, molecular docking and molecular dynamics simulation studies

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Abstract

Tuberculosis is one of the leading causes of death of at least one million people annually. The deadliest infectious disease has caused more than 120 million deaths in humans since 1882. The cell wall structure of Mycobacterium tuberculosis is important for survival in the host environment. InhA is the foremost target for the development of novel anti-tubercular agents. Therefore, we report pharmacophore-based virtual screening (ZINC and ASINEX databases) and molecular docking study (PDB Code: 4TZK) to identify and design potent inhibitors targeting to InhA. A five-point pharmacophore model AADHR_1 (with R2 = 0.97 and Q2 = 0.77) was developed by using 47 compounds with its reported MIC values. Further, to identify and design potent hit molecules based on lead identification and modification, generated hypothesis employed for virtual screening using ZINC and ASINEX databases. Predicted pyrazole derivatives further gauged for drug likeliness and docked against enoyl acyl carrier protein reductase to categorize the essential amino acid interactions to the active site of the enzyme. Structure elucidation of these synthesized compounds was carried out using IR, MS, 1H-NMR and 13C-NMR spectroscopy. Amongst all the synthesized compounds, some of the compounds 5a, 5c, 5d and 5e were found to be potent with their MIC ranging from 2.23 to 4.61 µM. Based on preliminary anti-tubercular activity synthesized potent molecules were further assessed for MDR-TB, XDR-TB and cytotoxic study.

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Acknowledgements

The authors are thankful to Maratha Mandal’s Dental College, Belgaum and NCL Pune for providing biological screening of these title compounds. The authors are also thankful to Schrodinger Inc. for providing help for the molecular dynamics simulation study.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, L. M. College of Pharmacy, Ahmedabad, Gujarat, 380009, India

    Palmi Modi, Shivani Patel & Mahesh Chhabria

  2. L. J. Institute of Pharmacy, L J University, Ahmedabad, Gujarat, 382 210, India

    Palmi Modi

  3. Division of Biological and Life Sciences, Ahmedabad University, Ahmedabad, Gujarat, 380009, India

    Shivani Patel

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Modi, P., Patel, S. & Chhabria, M. Discovery of newer pyrazole derivatives with potential anti-tubercular activity via 3D-QSAR based pharmacophore modelling, virtual screening, molecular docking and molecular dynamics simulation studies. Mol Divers 27, 1547–1566 (2023). https://doi.org/10.1007/s11030-022-10511-8

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