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P-Glycoprotein: A Critical Comparison of Models Depicting Mechanism of Drug Efflux and Role of Modulators

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Abstract

Permeability or P-glycoprotein (P-gp), present in both prokaryotes and eukaryotes is an essential protein belonging to the adenosine triphosphate (ATP) binding cassette transporter family. It functions as a protective barrier by extrusion of wide range of substrates including toxins, xenobiotic compounds and drugs from the cell. These are ubiquitous integral membrane proteins that have ATPase activity for substrate transport across the lipid membrane. The potential role of P-gp in efflux mechanism is to avoid drug accumulation and to provide intrinsic resistance to a broad range of anticancer compounds against sarcoma, breast cancer and certain types of leukemia. This review recapitulates the structural and functional aspects of core domains of P-gp. Furthermore, various proposed mechanisms of translocation of substrates across the membrane which explain the conformational changes in different domains upon ATP binding and hydrolysis. Another critical aspect focuses on different modulators and their mode of binding on P-gp which facilitates the inhibition of efflux mechanism. Ten models of drug efflux mechanism have been illustrated and a comparative account of their applicability and limitations given, paving way for further improvements. In the present study it has been observed that contrary to the earlier reported models where transmembrane domain is the preferred binding site of ligands resulting in their efflux through ATP hydrolysis at nucleotide binding domain (NBD) site. The more hydrophilic NBD appears to be the appropriate binding site for majority of the hydrophobic third and fourth generation modulators thus inhibiting the binding and hydrolysis of ATP resulting in inhibition of efflux.

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Acknowledgments

One of the authors (A. T.) is thankful to Director, Indian Institute of Information Technology, Allahabad for providing necessary facilities and Ministry of Human Resource Development (MHRD) for financial support. (R. K. K.) acknowledges the Indian Council of Medical Research (ICMR), New Delhi, India for providing financial support as Senior Research Fellowship (SRF) that was needed for completing the work. The authors report no conflict of interest.

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Authors and Affiliations

  1. Division of Applied Science & Indo-Russian Center for Biotechnology [IRCB], Indian Institute of Information Technology, Allahabad, 211012, India

    Anushree Tripathi & Rajesh Kumar Kesharwani

  2. Department of Bioinformatics, Central University of Bihar, Patna, 800014, India

    Durg Vijay Singh

  3. Centre of Biomedical Research, SGPGIMS Campus, Rae Bareli Road, Lucknow, 226014, India

    Krishna Misra

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  1. Anushree Tripathi
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Tripathi, A., Singh, D.V., Kesharwani, R.K. et al. P-Glycoprotein: A Critical Comparison of Models Depicting Mechanism of Drug Efflux and Role of Modulators. Proc. Natl. Acad. Sci., India, Sect. B Biol. Sci. 85, 359–375 (2015). https://doi.org/10.1007/s40011-014-0405-9

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