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.

Figure 1

Chemical structures of HDD, ADD and THD isolated from Dictyota species.

Figure 2

Theoretical toxicological profile of diterpenes HDD, ADD and THD and antiviral drugs delavirdine, etravirine, loviride and nevirapine.

Figure 3

Comparison of the docking complexes of ADD, HDD and THD with HIV-1 RT wild-type, respectively, including the parameters binding energy (BE, kcal/mol), number of interactions (NI), clusters (NC), and conformations on lowest energy cluster (CE) van der Waals (vdW) and hydrogen bonding (H-bond).

Figure 4

Molecular docking of THD on NNIBP of HIV-1 RT mutants (A) RT-1, (B) RT-2, (C) RT-3, (D) RT-4, (E) RT-5, (F) RT-7, (G) RT-8, (H) RT-9, (I) RT-10, (J) RT-11, (K) RT-12, (L) Superposition of all complexes. Ligand is shown in orange, residues involved on the interactions between THD and the enzyme are shown in gray, mutated residues are highlighted in cyan and hydrogen bonds in green.

Figure 5

Molecular docking of THD on NNIBP of HIV-1 RT-6 mutant. Ligand is shown in orange, residues involved on the interactions between THD and the enzyme are in gray, mutated residues are highlighted in cyan and hydrogen bonds in green.