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Mar. Drugs 2013, 11(11), 4127-4143; doi:10.3390/md11114127
Article

Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase

1
, 2
, 1,* , 3
, 3
, 4
, 5
, 6
 and 3,*
1 Laboratory of Antibiotics, Biochemistry, Education and Molecular Modeling (LABiEMol), Institute of Biology, Fluminense Federal University (UFF), Campus of Valonguinho, Niteroi, 24210-130, RJ, Brazil 2 Laboratory of Natural Products of Marine Algae, Institute of Biology, Fluminense Federal University (UFF), Campus of Valonguinho, Niteroi, 24210-130, RJ, Brazil 3 Laboratory of Molecular Modeling and QSAR (ModMolQSAR), Center for Health Sciences, Federal University of Rio de Janeiro (UFRJ), Faculty of Pharmacy, 21941-590, Rio de Janeiro, RJ, Brazil 4 Laboratory of Molecular Modeling (LabMMol), Chemistry Institute, Federal University of Rio de Janeiro (UFRJ), 21949-900, Rio de Janeiro, RJ, Brazil 5 Laboratory of Industrial Pharmaceutical Technology (LabTIF), Faculty of Pharmacy, Center for Health Sciences, Federal University of Rio de Janeiro (UFRJ), 21941-590, Rio de Janeiro, RJ, Brazil 6 Laboratory of Computational Medicinal Chemistry, Faculty of Pharmacy, Fluminense Federal University (UFF), 24241-000, Niteroi, RJ, Brazil
* Authors to whom correspondence should be addressed.
Received: 30 July 2013 / Revised: 11 September 2013 / Accepted: 2 October 2013 / Published: 29 October 2013
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Abstract

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, IC50 = 16.5 µM), (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial (HDD, IC50 = 10 µM) and (6R)-6-acetoxydichotoma-3,14-diene-1,17-dial (ADD, IC50 = 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 (ELUMO–EHOMO), 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.
Keywords: HIV-1; mutants; molecular docking; brown algae diterpenes; antiviral; reverse transcriptase HIV-1; mutants; molecular docking; brown algae diterpenes; antiviral; reverse transcriptase
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Miceli, L.A.; Teixeira, V.L.; Castro, H.C.; Rodrigues, C.R.; Mello, J.F.R.; Albuquerque, M.G.; Cabral, L.M.; de Brito, M.A.; de Souza, A.M.T. Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase. Mar. Drugs 2013, 11, 4127-4143.

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