Introduction: Inhibition of the reverse transcriptase (RT) enzyme of the 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. The parent molecule
and derivatives were then 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 drug-likeness screening by Swiss-ADME or at the 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 a fragment-based approach.