PT  - JOURNAL ARTICLE
AU  - Sindhu Varghese
AU  - Ashok Palaniappan
TI  - Computational Studies of P-Glycoprotein Polymorphisms in Antiepileptic Drug Resistance Mechanisms
AID  - 10.1101/095059
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 095059
4099  - http://biorxiv.org/content/early/2016/12/17/095059.short
4100  - http://biorxiv.org/content/early/2016/12/17/095059.full
AB  - The treatment of epilepsy using antiepileptogenic drugs is frequently complicated by drug resistance, leading to drug failure in more than one-third of cases. Human P-glycoprotein (hPGP), coded by MDR1 and belonging to the ABC superfamily, is a membrane efflux transporter that has been identified as an epileptogenic mediator. The ability of hPGP to bind a broad spectrum of substrates could be implicated in the emergence of drug resistance in epilepsy treatment. Single-nucleotide polymorphisms (SNPs) in MDR1 could compound the aberrant changes in hPGP activity causing and enhancing drug resistance. Bioinformatics approaches were used to assess the functional impact of 20 missense MDR1 polymorphisms and of these, five MDR1 polymorphisms were prioritised for further study. The structures of the wildtype and five mutant hPGP were modelled using the mouse PGP structure as the template. Docking studies of the wildtype and mutant PGP with four standard FDA-aprroved anti-epileptic drugs were carried out. Our results revealed that the drug binding site with respect to the wildtype protein was constant. However the hPGP mutant proteins displayed a repertoire of binding sites with stronger binding affinities towards the drug. Our studies indicate that specific polymorphisms in MDR1 could drive conformational changes of PGP structure, facilitating novel contacts with drug-substrates and eventually transporting the drug out of the cell, leading to pharmacoresistance.