Abstract

The transmembrane P-glycoprotein (P-gp), encoded by the multidrug resistance mutation 1 (MDR1) gene, acts as an energy-dependent drug-efflux pump involved in cellular drug excretion. The over-expression of P-gp is directly linked to multidrug resistance. Hence, the inhibition of its biosynthesis is a valuable approach to enhancing available therapies for numerous diseases. The purine-rich hexaloop hairpin belonging to P-glycoprotein 1 (PGY)/MDR1 mRNA is a target for antisense oligonucleotides to inhibit the expression of P-gp. The most efficient antisense oligomers are complementary to GGGAUG mRNA sequences belonging to the hairpin hexaloop. In this study, molecular docking and microsecond molecular dynamics (MD) simulations were performed to understand the binding process between this paradigmatic oligonucleotide and the target RNA. We evaluate the merits of the pitfalls of this in silico strategy and discuss its role in the rational design of novel therapeutic antisense oligonucleotides.