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.
Highlights
Acquired immunodeficiency syndrome (AIDS) was first identified in 1981 and, since 26 million people have died of HIV-1 related causes worldwide [1]
The HOMO-LUMO gap values (ELUMO-EHOMO) of the most active diterpene (THD) are much higher than the values of HDD, ADD and nevirapine (Table 1). This data suggest us that the HOMO-LUMO gap value may be important to antiviral profile since it is directly related to the stability of a molecule in which high HOMO-LUMO gap values indicates high internal stability
All theoretical toxicity evaluations of THD were better than those observed for delavirdine and etravirine, the antivirals currently used in HIV/AIDS therapy, presenting high mutagenic effects (Figure 2)
Summary
Acquired immunodeficiency syndrome (AIDS) was first identified in 1981 and, since 26 million people have died of HIV-1 related causes worldwide [1]. The major limitation of NNRTIs in clinical use is the HIV-1 RT mutations emergence that blocks the binding of the inhibitor [7]. Single mutations such as Leu100Ile, Lys101Glu, Lys103Asn, Val106Ala, Val108Ile, Tyr181Cys, Tyr188Leu, Gly190Ala, Pro225His, Phe227Leu and double mutations as Lys103Asn/Tyr181Cys, Lys103Asn/Val108Ile, Lys103Asn/. The first evidence of seaweed metabolites’ antiviral properties have been demonstrated over 50 years ago [18] It is only since 1970 that several research groups worldwide started systematic screening of extracts of algae to find products with biological activity and, in particular, an antiviral profile [19]. Studies showed that THD has low toxicity in the administered dose range In pursuit of this goal, we evaluated these diterpenes’ structure-activity relationship (SAR). The analysis of the binding mode of THD with the non-nucleoside inhibitor binding pocket (NNIBP) of RT wild-type and mutants was performed using a molecular docking approach
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