title: 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 (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.
authors.affiliation: Laboratory of Antibiotics, Biochemistry, Education and Molecular Modeling (LABiEMol), Institute of Biology, Fluminense Federal University (UFF), Campus of Valonguinho, Niteroi, 24210-130, RJ, Brazil. hcastrorangel@yahoo.com.br.
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Miceli
authors.forename: Valéria L
authors.initials: VL
authors.lastname: Teixeira
authors.forename: Helena C
authors.initials: HC
authors.lastname: Castro
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Rodrigues
authors.forename: Juliana F R
authors.initials: JF
authors.lastname: Mello
authors.forename: Magaly G
authors.initials: MG
authors.lastname: Albuquerque
authors.forename: Lucio M
authors.initials: LM
authors.lastname: Cabral
authors.forename: Monique A
authors.initials: MA
authors.lastname: de Brito
authors.forename: Alessandra M T
authors.initials: AM
authors.lastname: de Souza
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D004224:Diterpenes / Q000737:chemistry* / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation / Q000379:methods; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D004224:Diterpenes; D011480:Protease Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase