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.status: publishe

Concentration and pH dependent aggregation of hydrophobic drug molecules and relevance to oral bioavailability

We have examined selected physicochemical properties of compounds from the diaryltriazine/diarylpyrimidine (DATA/DAPY) classes of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and explored possible correlations with their bioavailability. In simple aqueous solutions designed to mimic the gastrointestinal (GI) environment of a fasting individual, all NNRTIs demonstrated formation of aggregates as detected by dynamic light scattering and electron microscopy. Under various conditions mimicking physiological transitions in the GI environment, aggregate size distributions were shown to depend on compound concentration and pH. NNRTIs with good absorption were capable of forming aggregates with hydrodynamic radii of /=250 nm at concentrations above 0.01 mM, probably representing precipitate. We propose a model in which the uptake rate into systemic circulation depends on having hydrophobic drug aggregates of appropriate size available for absorption at different locations within the GI tract.status: publishe

Structural basis of BLyS receptor recognition

B lymphocyte stimulator (BLyS), a member of the tumor necrosis factor (TNF) superfamily, is a cytokine that induces B-cell proliferation and immunoglobulin secretion. We have determined the three-dimensional structure of BLyS to 2.0 A resolution and identified receptor recognition segments using limited proteolysis coupled with mass spectrometry. Similar to other structurally determined TNF-like ligands, the BLyS monomer is a beta-sandwich and oligomerizes to form a homotrimer. The receptor-binding region in BLyS is a deeper, more pronounced groove than in other cytokines. The conserved elements on the 'floor' of this groove allow for cytokine recognition of several structurally related receptors, whereas variations on the 'walls' and outer rims of the groove confer receptor specificity.status: publishe