TitleThe roles of structural variability and amphiphilicity of
TMC278/rilpivirine in mechanisms of HIV drug resistance avoidance and enhanced oral bioavailability
NameFrenkel, Yulia (author), Olson, Wilma (chair), Arnold, Eddy (internal member), Stock, Ann (internal member), Levy, Ronald (internal member), Gallicchio, Emilio (outside member), Rutgers University, Graduate School - New Brunswick,
DescriptionNon-nucleoside reverse transcriptase inhibitors (NNRTIs) are small hydrophobic drug molecules that bind to a hydrophobic pocket of the HIV-1 reverse transcriptase (RT). A number of molecules from diarylpyrimidine (DAPY) class of NNRTIs have exceptional inhibitory properties against a broad range of known drug-resistant viral strains of HIV-1 and good oral bioavailability in humans. Biophysical, structural, and computational methods were applied to study DAPY NNRTIs with differing RT inhibitory and bioavailability properties with a goal to define the mechanisms by which the dual success of the selected DAPY NNRTIs is achieved.
Exceptional bioavailability properties of selected DAPY NNRTIs were hypothesized to stem from their ability to form self-formulated spherical drug aggregates, ~60 nm in diameter, that are trafficked from the gastrointestinal tract into systemic circulation through a lymphatic uptake pathway. Using dynamic light scattering (DLS) and electron microscopy (EM), formation of drug aggregates was demonstrated. Drug aggregation was determined to be surfactant independent. Based on this observation, it was hypothesized that the drug molecules were able to achieve surface-active properties. Using X-ray crystallography and all atom MD simulations of the drug aggregate/water interface it was determined that amphiphilic properties of the selected DAPY NNRTI molecules depend on the availability of the protonation site at the pyrimidine ring and structural variability of the drug molecules at the linker moieties.
Ability of the late phase DAPY NNRTI drug molecules to inhibit the broad range of drug-resistant HIV-1 mutants has been previously linked to the ability of the molecules to sample multiple binding modes within the binding pocket of HIV-1 RT (Das et al., 2004). Using computational methods, conformational sampling by TMC278 (a DAPY NNRTI in multiple Phase III trials) in the pocket of the wild-type and the mutant NNRTI-binding pocket (NNIBP) was evaluated. Results of this work support the concept that structural variability is important in overcoming drug resistance mechanisms.
We propose that the implementation of drug aggregation testing and the evaluation of torsional flexibility of highly hydrophobic compounds in the context of the lead identification strategies will allow for better selection of potent and orally bioavailable hydrophobic drug candidates.
NoteIncludes bibliographical references (139-146)
Noteby Yulia Frenkel
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.