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Cathepsin D inhibitors as potential therapeutics for breast cancer treatment: Molecular docking and bioevaluation against triple-negative and triple-positive breast cancers

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Abstract

The main aim of this study was to discover small molecule inhibitors against Cathepsin D (CatD) (EC.3.4.23.5), a clinically proven prognostic marker for breast cancer, and to explore the mechanisms by which CatD could be a useful therapeutic target for triple-positive and triple-negative breast cancers (TPBC & TNBC). The crystal structure of CatD at 2.5 Å resolution (PDB: 1LYB), which was complexed with Pepstatin A, was selected for computer-aided molecular modeling. The methods used in our study were pharmacophore modeling and molecular docking. Virtual screening was performed to identify small molecules from an in-house database and a large commercial chemical library. Cytotoxicity studies were performed on human normal cell line HEK293T and growth inhibition studies on breast adenocarcinoma cell lines, namely MCF-7, MDA-MB-231, SK-BR-3, and MDA-MB-468. Furthermore, RT-PCR analysis, in vitro enzyme assay, and cell cycle analysis ascertained the validity of the selected molecules. A set of 28 molecules was subjected to an in vitro fluorescence-based inhibitory activity assay, and among them six molecules exhibited \(>\)50 % inhibition at \(25\,\upmu \hbox {M}\). These molecules also exhibited good growth inhibition against TPBC and TNBC cancer types. Among them, molecules 1 and 17 showed single-digit micromolar \(\hbox {GI}_{50}\) values against MCF-7 and MDA-MB-231 cell lines.

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Acknowledgments

The authors gratefully acknowledge the Birla Institute of Technology and Sciences, Hyderabad for infrastructural facilities and DST for the INSPIRE fellowship.

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Authors and Affiliations

  1. Computer-Aided Drug Design Laboratory, Department of Pharmacy, Birla Institute of Technology & Science- Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad, 500078, Telangana, India

    Hasitha Shilpa Anantaraju, Madhu Babu Battu, Dharmarajan Sriram & Perumal Yogeeswari

  2. Incozen Therapeutics (P)Ltd, Shameerpet, R.R. District, Hyderabad, 500078, Telangana, India

    Srikant Viswanadha

  3. Yogee’S Bioinnovations Private Limited, Room No. 5, Technology Business Incubator, Birla Institute of Technology & Science- Pilani, Hyderabad Campus, Shameerpet, Hyderabad, 500078, Telangana, India

    Dharmarajan Sriram & Perumal Yogeeswari

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  1. Hasitha Shilpa Anantaraju
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  2. Madhu Babu Battu
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Correspondence to Perumal Yogeeswari.

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Anantaraju, H.S., Battu, M.B., Viswanadha, S. et al. Cathepsin D inhibitors as potential therapeutics for breast cancer treatment: Molecular docking and bioevaluation against triple-negative and triple-positive breast cancers. Mol Divers 20, 521–535 (2016). https://doi.org/10.1007/s11030-015-9645-8

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  • DOI: https://doi.org/10.1007/s11030-015-9645-8

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