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

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.

Dolabella‐3,7,18‐triene, the main constituent of the essential oil of the white lotus flower (Nymphaea lotus, Nymphaeaceae)

“…In 2014, three different isomers of 2,6‐dolabelladiene and three of 2,8(17)‐dolabelladiene were isolated from the brown alga Dictyota pfaffii and exhibited anti‐​HIV‐​1 activity. Dolabelladienetriol showed strong inhibitory activity against HIV‐1 reverse transcriptase enzyme and was thus deemed as a potential drug for antiretroviral therapy . Pardo‐Vargas et al .…”

Anti-HIV Drug Development Through Computational Methods

“…Researchers also speculate that RT mutations that confer drug resistance, but that are distant from the inhibitor-binding sites, often map to the unique RT-hybrid interface that undergoes conformational changes between the two catalytic states (3). The structureactivity relationship (SAR) of three RT inhibitors of marine origin (THD, HDD, and ADD) was approached with molecular modeling (4). Molecular docking studies of THD into HIV-1 RT wildtype and 12 different mutants showed that mutations have little influence in the positioning and interactions of THD (4).…”

“…The structureactivity relationship (SAR) of three RT inhibitors of marine origin (THD, HDD, and ADD) was approached with molecular modeling (4). Molecular docking studies of THD into HIV-1 RT wildtype and 12 different mutants showed that mutations have little influence in the positioning and interactions of THD (4). Following a rational drug design approach, a modification of THD was suggested to improve its biological activity (4).…”

“…Molecular docking studies of THD into HIV-1 RT wildtype and 12 different mutants showed that mutations have little influence in the positioning and interactions of THD (4). Following a rational drug design approach, a modification of THD was suggested to improve its biological activity (4). Five docking programs (Glide, FlexX, Molegro Virtual Docker, AutoDock Vina, and Hyde) were evaluated for their ability to predict the relative biological activity of 111 known 1,2,4-triazole and 76 other azole type HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) (5).…”

In Vitro Antiviral Activity Against Zika Virus From a Natural Product of the Brazilian Brown Seaweed Dictyota menstrualis

“…The marine natural products produced by these algae are cyclic diterpenes, many exclusive to the marine environment. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] The Zika virus (ZIKV) was first isolated in 1947 from the febrile rhesus monkey in the Zika Forest in Uganda. 17 The first case of human infection was originally described in 1954 in Africa after some sporadic infections in humans were recorded.…”