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

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 wel...

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Bibliographic Details
Published in:Current computer-aided drug design Vol. 17; no. 4; p. 538
Main Authors: Soltani, Arash, Hashemy, Seyed Isaac, Avval, Farnaz Zahedi, Rafatpanah, Houshang, Rezaee, Seyed Abdolrahim, Griffith, Renate, Mashkani, Baratali
Format: Journal Article
Language:English
Published: United Arab Emirates 01.01.2021
Subjects:
Anti-HIV Agents - pharmacology
HIV Infections - drug therapy
HIV-1
Humans
Molecular Docking Simulation
Reverse Transcriptase Inhibitors - pharmacology
gold
interaction energy
molecular docking
HIV-1 RT
reverse transcriptase
NNRTIs
ISSN:1875-6697, 1875-6697
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Summary: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. 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. 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. In this study, we have identified and proposed some novel molecules with improved binding capacity for HIV RT using a fragment-based approach.
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ISSN:1875-6697
1875-6697
DOI:10.2174/1573409916666200628103359