Molecular dynamics study of non-nucleoside reverse transcriptase inhibitor 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (TMC278/rilpivirine) aggregates: correlation between amphiphilic properties of the drug and oral bioavailability.

The non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278/rilpivirine is an anti-AIDS therapeutic agent with high oral bioavailability despite its high hydrophobicity. Previous studies established a correlation between ability of the drug molecule to form stable, homogeneous populations of spherical nanoparticles (approximately 100-120 nm in diameter) at low pH in surfactant-independent fashion and good oral bioavailability. Here, we hypothesize that the drug is able to assume surfactant-like properties under physiologically relevant conditions, thus facilitating formation of nanostructures in the absence of other surfactants. The results of all-atom molecular dynamics simulations indeed show that protonated drug molecules behave as surfactants at the water/aggregate interface while neutral drug molecules assist aggregate packing via conformational variability. Our simulation results suggest that amphiphilic behavior at low pH and intrinsic flexibility influence drug aggregation and are believed to play critical roles in the favorable oral bioavailability of hydrophobic drugs.