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Identification of structural requirements of estrogen receptor modulators using pharmacoinformatics techniques for application to estrogen therapy

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Abstract

In this study, we explored the structural requirements of known estrogen receptor modulators for biological activity using pharmacoinformatics approaches to elucidate critical functionalities for new, potent and less toxic chemical agents for successful application in estrogen therapy. For this purpose, a group of nonsteroidal ligands 7-thiabicyclo[2.2.1]hept-2-ene-7-oxide derivatives were collected from the literature to perform quantitative structure–activity relationship (QSAR), pharmacophore and molecular docking studies. The 2D QSAR models (R 2 α  = 0.857, se α  = 0.370, Q 2 α  = 0.848, R 2pred−α  = 0.675, s pα  = 0.537; R 2 β  = 0.874, se β  = 0.261, Q 2 β  = 0.859, R 2pred−β  = 0.659, s pβ  = 0.408) explained that hydrophobicity and molar refractivity were crucial for binding affinity in both α- and β-subtypes. The space modeling study (R 2 α  = 0.955, se α  = 1.311, Q 2 α  = 0.932, R 2pred−α  = 0.737, s pα  = 0.497; R 2 β  = 0.885, se β  = 1.328, Q 2 β  = 0.878, R 2pred−β  = 0.769, s pβ  = 0.336) revealed the importance of HB donor and hydrophobic features for both subtypes, whereas HB acceptor and aromatic ring were critical for α- and β-subtypes, respectively. The functionalities developed in the QSAR and pharmacophore studies were substantiated by molecular docking studies which provided the preferred orientation of ligands for effective interaction at the active site cavity.

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Acknowledgments

Md.A. Islam and T.S. Pillay were funded by the University of Pretoria Vice Chancellor’s postdoctoral fellowship and National Research Foundation (NRF), South Africa Innovation postdoctoral fellowship schemes.

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    Authors and Affiliations

    1. Department of Chemical Pathology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Arcadia, Pretoria, 0007, South Africa

      Md. Ataul Islam & Tahir S. Pillay

    2. G.H.Patel Post Graduate Department of Computer Science and Technology (GDCST), Sardar Patel University, Anand, Gujarat, India

      Darshakkumar Ashokbhai Patel & Savansinh Ghanshyamsinh Rathod

    3. Department of Bioinformatics, Rajiv Gandhi Institute of Information Technology and Biotechnology, Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, India

      Preeti Chunarkar

    4. National Health Laboratory Service, Tshwane Academic Division, Pretoria, South Africa

      Md. Ataul Islam & Tahir S. Pillay

    5. Division of Chemical Pathology, Faculty of Health Sciences, University of Cape Town, Rondebosch, Cape Town, South Africa

      Tahir S. Pillay

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    Md. Ataul Islam, Darshakkumar Ashokbhai Patel and Savansinh Ghanshyamsinh Rathod have contributed equally to this work.

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    Islam, M.A., Patel, D.A., Rathod, S.G. et al. Identification of structural requirements of estrogen receptor modulators using pharmacoinformatics techniques for application to estrogen therapy. Med Chem Res 25, 407–421 (2016). https://doi.org/10.1007/s00044-015-1496-4

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