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Application of Molecular Docking for the Development of Improved HIV-1 Reverse Transcriptase Inhibitors.
Curr Comput Aided Drug Des. 2020 Jun 27 [Online ahead of print]CC

Abstract

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.

Authors+Show Affiliations

Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran.Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad. Iran.Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran.Department of Medical Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran.Department of Medical Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran.School of Chemistry, UNSW Sydney, Kensington, NSW 2052. Australia.Bioinformatics Research Group, Mashhad University of Medical Sciences, Mashhad. Iran.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32598265

Citation

Soltani, Arash, et al. "Application of Molecular Docking for the Development of Improved HIV-1 Reverse Transcriptase Inhibitors." Current Computer-aided Drug Design, 2020.
Soltani A, Hashemy SI, Avval FZ, et al. Application of Molecular Docking for the Development of Improved HIV-1 Reverse Transcriptase Inhibitors. Curr Comput Aided Drug Des. 2020.
Soltani, A., Hashemy, S. I., Avval, F. Z., Rafatpanah, H., Rezaee, S. A., Griffith, R., & Mashkani, B. (2020). Application of Molecular Docking for the Development of Improved HIV-1 Reverse Transcriptase Inhibitors. Current Computer-aided Drug Design. https://doi.org/10.2174/1573409916666200628103359
Soltani A, et al. Application of Molecular Docking for the Development of Improved HIV-1 Reverse Transcriptase Inhibitors. Curr Comput Aided Drug Des. 2020 Jun 27; PubMed PMID: 32598265.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Application of Molecular Docking for the Development of Improved HIV-1 Reverse Transcriptase Inhibitors. AU - Soltani,Arash, AU - Hashemy,Seyed Isaac, AU - Avval,Farnaz Zahedi, AU - Rafatpanah,Houshang, AU - Rezaee,Seyed Abdolrahim, AU - Griffith,Renate, AU - Mashkani,Baratali, Y1 - 2020/06/27/ PY - 2019/12/18/received PY - 2020/05/14/revised PY - 2020/05/24/accepted PY - 2020/6/30/entrez KW - Gold KW - HIV-1 RT KW - Interaction energy KW - Molecular docking KW - NNRTIs KW - Reverse transcriptase JF - Current computer-aided drug design JO - Curr Comput Aided Drug Des N2 - 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. SN - 1875-6697 UR - https://www.unboundmedicine.com/medline/citation/32598265/Application_of_Molecular_Docking_for_the_Development_of_Improved_HIV-1_Reverse_Transcriptase_Inhibitors L2 - http://www.eurekaselect.com/183242/article DB - PRIME DP - Unbound Medicine ER -
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