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Design and development of novel inhibitors of aldo-ketoreductase 1C1 as potential lead molecules in treatment of breast cancer

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Abstract

Aldo–keto reductase 1C1 (AKR1C1) is a hydroxysteroid dehydrogenase, known to inactivate the biologically active progesterone into its corresponding 20 α-hydroxyprogesterone. Increased expression of the AKR1C1 gene in oncogenesis is linked with resistance to various anticancer agents and hence it is considered as an emerging drug target for the design and developing the novel anticancer drugs. We have performed QSAR pharmacophore modeling for AKR1C1 inhibitors followed by a virtual screening of ~ 59,000 compounds present at the Maybridge database. The screened compounds were refined using drug-like filters of Lipinski rule, ADMET plot, molecular docking and scoring and subsequently top 20 hits were selected. Selected compounds were subjected to the in vitro for AKR1C1 inhibition assay and best seven compounds bearing excellent binding affinity to the AKR1C1 were finally selected. The identified compounds may be exploited in hit-to-lead development and may also prove as an interventional strategy in preventing a pre-term birth due to declining levels of progesterone.

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Acknowledgements

We acknowledge the fellowship grant from the Department of Health & Research, MoHFW, New Delhi, and to the Dr B R. Ambedkar Center for Biomedical Research (DU) for providing the Bioinformatics Infrastructure Facility (BIF).

Funding

This work was supported by the Department of Health & Research, MoHFW, New Delhi research grant (No: V.25011/450-HRD/2016-h).

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Authors and Affiliations

  1. Molecular Biology Research Lab, Department of Zoology, Deshbandhu College, University of Delhi, New Delhi, 110019, India

    Priyanka Verma & Indrakant K. Singh

  2. Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India

    Md. Imtaiyaz Hassan

  3. Department of Botany, Hansraj College, University of Delhi, New Delhi, 110007, India

    Archana Singh

  4. Deshbandhu College, University of Delhi, New Delhi, 110019, India

    Indrakant K. Singh

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  1. Priyanka Verma
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Verma, P., Hassan, M.I., Singh, A. et al. Design and development of novel inhibitors of aldo-ketoreductase 1C1 as potential lead molecules in treatment of breast cancer. Mol Cell Biochem 476, 2975–2987 (2021). https://doi.org/10.1007/s11010-021-04134-0

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