RESEARCH ARTICLE
Computational Pharmacogenetics of P-Glycoprotein Mediated Antiepileptic Drug Resistance
Sindhu Varghese1, Ashok Palaniappan2, *
Article Information
Identifiers and Pagination:
Year: 2018Volume: 11
First Page: 197
Last Page: 207
Publisher ID: TOBIOIJ-11-197
DOI: 10.2174/1875036201811010197
Article History:
Received Date: 21/4/2018Revision Received Date: 12/7/2018
Acceptance Date: 27/7/2018
Electronic publication date: 31/08/2018
Collection year: 2018
open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background:
The treatment of epilepsy using antiepileptogenic drugs is complicated by drug resistance, resulting in treatment failure in more than one-third of cases. Human P-glycoprotein (hPGP; MDR1) is a known epileptogenic mediator.
Methods:
Given that experimental investigations have suggested a role for pharmacogenetics in this treatment failure, it would be of interest to study hPGP polymorphisms that might contribute to the emergence of drug resistance. Changes in protein functional activity could result from mutations as well as altered abundance. Bioinformatics approaches were used to assess and rank the functional impact of 20 missense MDR1 polymorphisms and the top five were selected. The structures of the wildtype and variant hPGP were modelled based on the mouse PGP structure. Docking studies of the wildtype and variant hPGP with four standard anti-epileptic drugs were carried out.
Results:
Our results revealed that the drug binding site with respect to the wildtype protein was uniform. However, the variant hPGP proteins displayed a repertoire of binding sites with stronger binding affinities towards the drug.
Conclusion:
Our studies indicated that specific polymorphisms in MDR1 could drive conformational changes of PGP structure, facilitating altered contacts with drug-substrates and thus modifying their bioavailability. This suggests that MDR1 polymorphisms could actively contribute to the emergence of pharmaco-resistance in antiepileptic therapy.