Application of Molecular Docking for the Development of Improved HIV-1 Reverse Transcriptase Inhibitors

Author(s): Arash Soltani, Seyed Isaac Hashemy, Farnaz Zahedi Avval, Houshang Rafatpanah, Seyed Abdolrahim Rezaee, Renate Griffith, Baratali Mashkani*

Journal Name: Current Computer-Aided Drug Design

Volume 17 , Issue 4 , 2021


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Abstract:

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.

Keywords: HIV-1 RT, reverse transcriptase, molecular docking, interaction energy, gold, NNRTIs.

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Article Details

VOLUME: 17
ISSUE: 4
Year: 2021
Published on: 27 June, 2020
Page: [538 - 549]
Pages: 12
DOI: 10.2174/1573409916666200628103359
Price: $65

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