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In silico designing of peptide inhibitors against pregnane X receptor: the novel candidates to control drug metabolism

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Abstract

Drug-induced pregnane X receptor (PXR) activation may be unavoidable with some treatments. Besides, drug-induced PXR activation may lead to drug interactions with a number of treatments. Human PXR antagonists represent a means to counteract such interactions. Indeed, the ideal small molecule would have good drug-like properties, but be devoid of nonspecific cell-target effects and ability to induce cytotoxicity. Researchers assess on the possibility of deriving inhibitory peptides, which are derived from interfaces of “protein–protein interactions” (PPIs) could inhibit interactions of their origin domain by mimicking its mode of binding to cognate partners. Such peptides could serve as promising leads for rational design of inhibitory drugs. In this study, In silico designing of peptide inhibitors and peptidomimetics against PPIs was done to prevent unwanted drug metabolisms caused by PXR activation. In sum, no designed peptides had considerable higher energy of interactions and more H-bonds with the receptor compared to the SRC-1 peptides. Hence, none of the designed peptides are predicted to be more active against the target receptor. However, compared to the SRC-1 peptide, a designed peptidomimetic (mimetic3) had considerable higher energy of interactions with the receptor. It formed five H-bonds with PXR that was equal to the number of H-bonds that SRC-1 formed with the receptor. Therefore, by designing such mimetics, it would be probable to have a realistic chance of achieving peptides with improved binding affinity compared to SRC-1 and consequently prevent the unwanted drug metabolisms caused by PXR activation.

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  1. Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, P.O.Box 19569‑44413, Tehran, Iran

    Tayebeh Farhadi

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  1. Tayebeh Farhadi
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Farhadi, T. In silico designing of peptide inhibitors against pregnane X receptor: the novel candidates to control drug metabolism. Int J Pept Res Ther 24, 409–420 (2018). https://doi.org/10.1007/s10989-017-9627-z

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