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Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase
AIDS is a pandemic responsible for more than 35 million deaths. The emergence of resistant mutations due to drug use is the biggest cause of treatment failure. Marine organisms are sources of different molecules, some of which offer promising HIV-1 reverse transcriptase (RT) inhibitory activity, suc...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853719/ https://www.ncbi.nlm.nih.gov/pubmed/24172210 http://dx.doi.org/10.3390/md11114127 |
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author | Miceli, Leonardo A. Teixeira, Valéria L. Castro, Helena C. Rodrigues, Carlos R. Mello, Juliana F. R. Albuquerque, Magaly G. Cabral, Lucio M. de Brito, Monique A. de Souza, Alessandra M. T. |
author_facet | Miceli, Leonardo A. Teixeira, Valéria L. Castro, Helena C. Rodrigues, Carlos R. Mello, Juliana F. R. Albuquerque, Magaly G. Cabral, Lucio M. de Brito, Monique A. de Souza, Alessandra M. T. |
author_sort | Miceli, Leonardo A. |
collection | PubMed |
description | AIDS is a pandemic responsible for more than 35 million deaths. The emergence of resistant mutations due to drug use is the biggest cause of treatment failure. Marine organisms are sources of different molecules, some of which offer promising HIV-1 reverse transcriptase (RT) inhibitory activity, such as the diterpenes dolabelladienotriol (THD, IC(50) = 16.5 µM), (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial (HDD, IC(50) = 10 µM) and (6R)-6-acetoxydichotoma-3,14-diene-1,17-dial (ADD, IC(50) = 35 µM), isolated from a brown algae of the genus Dictyota, showing low toxicity. In this work, we evaluated the structure-activity relationship (SAR) of THD, HDD and ADD as anti HIV-1 RT, using a molecular modeling approach. The analyses of stereoelectronic parameters revealed a direct relationship between activity and HOMO (Highest Occupied Molecular Orbital)-LUMO (Lowest Unoccupied Molecular Orbital) gap (E(LUMO)–E(HOMO)), where antiviral profile increases with larger HOMO-LUMO gap values. We also performed molecular docking studies of THD into HIV-1 RT wild-type and 12 different mutants, which showed a seahorse conformation, hydrophobic interactions and hydrogen bonds with important residues of the binding pocket. Based on in vitro experiments and docking studies, we demonstrated that mutations have little influence in positioning and interactions of THD. Following a rational drug design, we suggest a modification of THD to improve its biological activity. |
format | Online Article Text |
id | pubmed-3853719 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-38537192013-12-06 Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase Miceli, Leonardo A. Teixeira, Valéria L. Castro, Helena C. Rodrigues, Carlos R. Mello, Juliana F. R. Albuquerque, Magaly G. Cabral, Lucio M. de Brito, Monique A. de Souza, Alessandra M. T. Mar Drugs Article AIDS is a pandemic responsible for more than 35 million deaths. The emergence of resistant mutations due to drug use is the biggest cause of treatment failure. Marine organisms are sources of different molecules, some of which offer promising HIV-1 reverse transcriptase (RT) inhibitory activity, such as the diterpenes dolabelladienotriol (THD, IC(50) = 16.5 µM), (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial (HDD, IC(50) = 10 µM) and (6R)-6-acetoxydichotoma-3,14-diene-1,17-dial (ADD, IC(50) = 35 µM), isolated from a brown algae of the genus Dictyota, showing low toxicity. In this work, we evaluated the structure-activity relationship (SAR) of THD, HDD and ADD as anti HIV-1 RT, using a molecular modeling approach. The analyses of stereoelectronic parameters revealed a direct relationship between activity and HOMO (Highest Occupied Molecular Orbital)-LUMO (Lowest Unoccupied Molecular Orbital) gap (E(LUMO)–E(HOMO)), where antiviral profile increases with larger HOMO-LUMO gap values. We also performed molecular docking studies of THD into HIV-1 RT wild-type and 12 different mutants, which showed a seahorse conformation, hydrophobic interactions and hydrogen bonds with important residues of the binding pocket. Based on in vitro experiments and docking studies, we demonstrated that mutations have little influence in positioning and interactions of THD. Following a rational drug design, we suggest a modification of THD to improve its biological activity. MDPI 2013-10-29 /pmc/articles/PMC3853719/ /pubmed/24172210 http://dx.doi.org/10.3390/md11114127 Text en © 2013 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Article Miceli, Leonardo A. Teixeira, Valéria L. Castro, Helena C. Rodrigues, Carlos R. Mello, Juliana F. R. Albuquerque, Magaly G. Cabral, Lucio M. de Brito, Monique A. de Souza, Alessandra M. T. Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase |
title | Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase |
title_full | Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase |
title_fullStr | Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase |
title_full_unstemmed | Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase |
title_short | Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase |
title_sort | molecular docking studies of marine diterpenes as inhibitors of wild-type and mutants hiv-1 reverse transcriptase |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853719/ https://www.ncbi.nlm.nih.gov/pubmed/24172210 http://dx.doi.org/10.3390/md11114127 |
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