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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

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Received: 30 July 2013; in revised form: 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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MDPI and ACS Style

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.

AMA Style

Miceli LA, Teixeira VL, Castro HC, Rodrigues CR, Mello JFR, Albuquerque MG, Cabral LM, de Brito MA, de Souza AMT. Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase. Marine Drugs. 2013; 11(11):4127-4143.

Chicago/Turabian Style

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. 2013. "Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase." Mar. Drugs 11, no. 11: 4127-4143.



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