Introoduction:
Inhibition of the reverse transcriptase (RT) enzyme of human immunodeficiency virus (HIV) by low molecular weight inhibitors is still an active area of research. Here, protein-ligand interactions and possible binding modes of novel
compounds with the HIV-1 RT binding pocket (the wild-type as well as Y181C and K103N mutants) were obtained and
discussed.
Methods:
A molecular fragment-based approach using FDA-approved drugs were followed to design novel chemical derivatives using delavirdine, efavirenz, etravirine and rilpivirine as the scaffolds. The drug-likeliness of the derivatives was
evaluated using Swiss-ADME. Then the parent molecule and derivatives were docked into the binding pocket of related
crystal structures (PDB ID: 4G1Q, 1IKW, 1KLM and 3MEC). Genetic Optimization for Ligand Docking (GOLD) Suite
5.2.2 software was used for docking and the results analyzed in the Discovery Studio Visualizer 4. A derivative was chosen
for further analysis, if it passed drug-likeliness and the docked energy was more favorable than that of its parent molecule.
Out of the fifty-seven derivatives, forty-eight failed in druglikeness screening by Swiss-ADME or in docking stage.
Results:
The final results showed that the selected compounds had higher predicted binding affinities than their parent scaffolds in both wild-type and the mutants. Binding energy improvement was higher for the structures designed based on second-generation NNRTIs (etravirine and rilpivirine) than the first-generation NNRTIs (delavirdine and efavirenz). For example, while the docked energy for rilpivirine was -51 KJ/mol, it was improved for its derivatives RPV01 and RPV15 up to
-58.3 and -54.5 KJ/mol, respectively.
Conclusion:
In this study, we have identified and proposed some novel molecules with improved binding capacity for HIV
RT using fragment-based approach.
Crystal Structure oftert-Butyldimethylsilyl-spiroaminooxathioledioxide-thymine (TSAO-T) in Complex with HIV-1 Reverse Transcriptase (RT) Redefines the Elastic Limits of the Non-nucleoside Inhibitor-Binding Pocket