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Design and evaluation of pyrimidine derivatives as potent inhibitors of ABCG2, a breast cancer resistance protein

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Abstract

The protein ATP-binding cassette subfamily G member 2 (ABCG2) is one of the major factors behind multidrug resistance (MDR) in breast cancer. We performed three-dimensional quantitative structure–activity relationship (3D-QSAR) modelling, docking, and molecular dynamics (MD) simulation to design pyrimidine-based ABCG2 antagonists. The developed QSAR model (r2 = 0.92, q2 = 0.82, and good cross-validated r2 = 0.73) dictate requirement of electrostatic, and hydrophobic fields for modulating bioactivity. Based on this rationale, we designed and screened 1010 new compounds, among them 2 (ND-510 and ND-500) exhibit excellent drug-like features. Comparative molecular docking, MM/GBSA and ADMET profiles were determined to understand the interactive poses, affinity, and drug-likeness of the designed compounds. Furthermore, MD simulations were performed with the ABCG2 receptor, and the results were compared with the two earlier synthesized active compounds. The outcomes of the study will help researchers to develop new antagonists for treatment of MDR breast cancer.

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Acknowledgements

SA is thankful for the IFTM University, Jamia Millia Islamia and Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology for providing the working environment and excellent infrastructure to peruse the doctorial research work.

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Authors and Affiliations

  1. School of Biotechnology, College of Engineering and Technology, IFTM University, Lodhipur-Rajput, Delhi Road (NH-24), Moradabad, Uttar Pradesh, 244102, India

    Shahnawaz Ahmad & Neeraj Dwivedi

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

    Md. Imtaiyaz Hassan & Asimul Islam

  3. Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi, 110067, India

    Dinesh Gupta

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  1. Shahnawaz Ahmad
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  2. Md. Imtaiyaz Hassan
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  3. Dinesh Gupta
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  4. Neeraj Dwivedi
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  5. Asimul Islam
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Contributions

SA contributed to extensive in-silico exercises, MD simulations investigations, and original draft write-up in the manuscript. MIH contributed to corrections in the manuscript. DG contributed to review and corrections in the manuscript. ND contributed major inputs, reviews, and corrections in the manuscript. AI contributed to the final review, correspondence, and corrections in the manuscript.

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Correspondence to Neeraj Dwivedi or Asimul Islam.

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None of the authors have conflicts and declare no competing interests.

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Ahmad, S., Hassan, M.I., Gupta, D. et al. Design and evaluation of pyrimidine derivatives as potent inhibitors of ABCG2, a breast cancer resistance protein. 3 Biotech 12, 182 (2022). https://doi.org/10.1007/s13205-022-03231-1

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  • DOI: https://doi.org/10.1007/s13205-022-03231-1

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