Computational Pharmacogenetics of P-Glycoprotein Mediated Antiepileptic Drug Resistance

Sindhu Varghese, Ashok Palaniappan
2018 The Open Bioinformatics Journal  
The treatment of epilepsy using antiepileptogenic drugs is complicated by drug resistance, resulting in treatment failure in more than one-third of cases. Human Pglycoprotein (hPGP; MDR1 ) is a known epileptogenic mediator. 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
more » ... ty could result from point 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 mutant hPGP were modelled based on the mouse PGP structure. Docking studies of the wildtype and mutant hPGP with four standard anti-epileptic drugs were carried out. Our results revealed that the drug binding site with respect to the wildtype protein was uniform. However the mutant hPGP proteins displayed a repertoire of binding sites with stronger binding affinities towards the drug. Our studies indicated that specific polymorphisms in MDR1 could drive conformational changes of PGP structure, facilitating altered contacts with drug-substrates and resulting in drug extrusion. This suggests that MDR1 polymorphisms could play an active role in modifying drug bioavailability, leading to pharmacoresistance in antiepileptic chemotherapy.
doi:10.2174/1875036201811010197 fatcat:7l2qvppyzfbwxfa2mwggxf542a