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Prospective Drug Candidates as Human Multidrug Transporter ABCG2 Inhibitors: an In Silico Drug Discovery Study

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Abstract

Breast cancer resistance protein (ABCG2) is a human ATP-binding cassette (ABC) that plays a paramount role in multidrug resistance (MDR) in cancer therapy. The discovery of ABCG2 inhibitors could assist in designing unprecedented therapeutic strategies for cancer treatment. There is as yet no approved drug targeting ABCG2, although a large number of drug candidates have been clinically investigated. In this work, binding affinities of 181 drug candidates in clinical-trial or investigational stages as ABCG2 inhibitors were inspected using in silico techniques. Based on available experimental data, the performance of AutoDock4.2.6 software was first validated to predict the inhibitor-ABCG2 binding mode and affinity. Combined molecular docking calculations and molecular dynamics (MD) simulations, followed by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations, were then performed to filter out the studied drug candidates. From the estimated docking scores and MM-GBSA binding energies, six auspicious drug candidates—namely, pibrentasvir, venetoclax, ledipasvir, avatrombopag, cobicistat, and revefenacin—exhibited auspicious binding energies with value < −70.0 kcal/mol. Interestingly, pibrentasvir, venetoclax, and ledipasvir were observed to show even higher binding affinities with the ABCG2 transporter with binding energies of < −80.0 kcal/mol over long MD simulations of 100 ns. The stabilities of these three promising candidates in complex with ABCG2 transporter were demonstrated by their energetics and structural analyses throughout the 100 ns MD simulations. The current study throws new light on pibrentasvir, venetoclax, and ledipasvir as curative options for multidrug resistant cancers by inhibiting ABCG2 transporter.

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Acknowledgements

M.F.M. extends his appreciation to the Deanship of Scientific Research at King Khalid University for funding this work under grant no. (R.G.P.1/143/42). The computational work was completed with resources supported by the Science and Technology Development Fund, STDF, Egypt, Grants No. 5480 & 7972.

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Authors and Affiliations

  1. Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, Egypt

    Mahmoud A. A. Ibrahim, Esraa A. A. Badr, Alaa H. M. Abdelrahman & Gamal A. H. Mekhemer

  2. Department of Biology, College of Science, University of Hafr Al Batin, Hafr Al Batin, Saudi Arabia

    Nahlah Makki Almansour

  3. Science and Technology Unit (STU), Umm Al-Qura University, Makkah, Saudi Arabia

    Ahmed M. Shawky

  4. Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia

    Faris Alrumaihi

  5. Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia

    Mahmoud F. Moustafa

  6. Department of Botany & Microbiology, Faculty of Science, South Valley University, Qena, Egypt

    Mahmoud F. Moustafa

  7. Molecular Genetics and Genome Mapping Laboratory, Genome Mapping Department, Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center (ARC), Giza, Egypt

    Mohamed A. M. Atia

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  1. Mahmoud A. A. Ibrahim
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Ibrahim, M.A.A., Badr, E.A.A., Abdelrahman, A.H.M. et al. Prospective Drug Candidates as Human Multidrug Transporter ABCG2 Inhibitors: an In Silico Drug Discovery Study. Cell Biochem Biophys 79, 189–200 (2021). https://doi.org/10.1007/s12013-021-00985-y

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