Quantum Chemical Study of Molecular Recognition between Etravirine/Rilpivirine and the HIV-1 Reverse Transcriptase

Sada Alqahtani, Hui Yang, Xiche Hu
2017 Madridge Journal of Novel Drug Research  
Second generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) etravirine and rilpivirine are essential components in the highly active antiretroviral therapy for the treatment of patients infected with human immunodeficiency virus type 1 (HIV-1). They are highly potent drugs against wild-type viruses and have exhibited excellent antiviral activities against some NNRTIs-resistant HIV-1 variants. In order to understand the underlying mechanism behind their robust resistance profile
more » ... comparison with the first generation NNRTIs nevirapine and efavirenz, it is necessary to quantitatively analyze their binding pockets in the wild-type HIV-1 reverse transcriptase (RT) and various HIV-1 RT mutants at the molecular level. Therefore, a high-level ab initio quantum chemical analysis was performed to decipher the molecular determinants for recognition of etravirine and rilpivirine by the wild-type RT and some RT mutants (K103N, K103N/Y181C, and K103N/L100I) of clinically important virus strains. Pair wise intermolecular interaction analysis determined the contribution of individual intermolecular interactions to the binding affinities between the second generation NNRTIs (etravirine or rilpivirine) and several variants of RTs, including the wild-type RT, and clinically relevant K103N, K103N/Y181C, and K103N/L100I mutant RTs. This quantitative analysis led to the identification of drug-protein interactions that persist despite mutations as well as to the evaluation of stabilization energy losses upon mutations. The results of this study enhanced our understanding of the molecular level mechanisms by which the second generation NNRTI drugs maintain their strong binding to mutant RTs. It is hoped that findings of this work would have a direct impact on designing new NNRTIs that are even more resilient to mutations in future.
doi:10.18689/mjndr-1000105 fatcat:jwwbw35bmjhkvk5cnyhkq55jda