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A computational study of CYP3A4 mediated drug interaction profiles for anti-HIV drugs

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Abstract

Molecular docking is a reliable method with which to identify the binding conformations of substrates, inducers and inhibitors of cytochrome P450 (CYP) enzymes. We used the docking method to explore possible binding modes of an entry inhibitor (maraviroc) and non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz and etravirine) to cytochrome P450 3A4 (CYP3A4). In addition, docking results were compared with the binding conformations of HIV protease drugs to infer the binding site residues and potential drug–drug interaction profiles for combination therapy in the treatment of AIDS. We observed that efavirenz and etravirine induce metabolism of co-administered drugs by binding to a unique position in the active site of CYP3A4. Dosage adjustment is required for delavirdine and maraviroc when combined with HIV protease drugs. The present results are in good agreement with experimental data from drug interaction profiles. The information provided in this paper will be helpful in furthering our understanding the functions of CYP3A4, and could aid in the design of new drugs that would be metabolized easily without having any drug–drug interaction profile.

The docked poses of etravirine (ETR) inside the active site of cytochrome P450 3A4 (CYP3A4). The binding site residues are colored by atom type: gray carbon, red oxygen, blue nitrogen, cyan hydrogen, yellow sulfur. The sticks of the ligands and heme are colored in green.

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Acknowledgments

P.P. Mathur acknowledges receipt of financial support from the Department of Biotechnology (DBT), and the Department of Information Technology (DIT), Government of India, New Delhi, India.

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Authors and Affiliations

  1. Centre of Excellence in Bioinformatics, School of Life Sciences, Pondicherry University, Pondicherry, 605014, India

    Jayakanthan Mannu, Pranitha Jenardhanan & Premendu P. Mathur

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  1. Jayakanthan Mannu
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  2. Pranitha Jenardhanan
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Correspondence to Premendu P. Mathur.

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Mannu, J., Jenardhanan, P. & Mathur, P.P. A computational study of CYP3A4 mediated drug interaction profiles for anti-HIV drugs. J Mol Model 17, 1847–1854 (2011). https://doi.org/10.1007/s00894-010-0890-6

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  • DOI: https://doi.org/10.1007/s00894-010-0890-6

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