Abstract
It is of interest to elucidate the binding mode analysis of 18 sulphonated flavones in the non nucleoside inhibitory binding pocket of the HIV-1 reverse transcriptase (PDB ID: 1RTD). We further compared them with the known Non Nucleosidic Reverse Transcriptase Inhibitors (NNRTI) drug molecules such as delaviridine, nevirapine and etravirine. Molecular docking studies of sulphonated flavones were performed in the binding pocket of reverse transcriptase using the PatchDock server. The flavones have different binding energies with RT and the atomic contact energy (ACE) value of sulfonated flavones range from-389 to-231 Kcal/mol while docking of the commercialized NNRTI showed the ACE value range from -486 to -224 Kcal/mol. This shows that most sulfonated flavones have ACE similar to the known NNRTI. Thus, seven compounds (FS-6, FS-7, FS-8, FS-9, FS-14, FS-15, FS-17) were reported as potent, selective, orally bio available, and nontoxic lead based on ADMET screening and effective binding analysis in the active site of the reverse transcriptase (PDB ID: 1RTD) for further consideration. We further document that compounds (FS-1, FS-10, FS-4 and FS-12) have unfavorable binding features to be considered as leads.
Highlights
Flavones are a subclass of natural compounds belonging to the class of flavonoids which are secondary metabolites very common in plant kingdom and responsible for numerous biological activities
Flavonoids are becoming the focus of medical research, they were used in many therapeutic application, such as anti-inflammatory, antimicrobial and anti-carcinogenic agents, others flavonoids were confirmed to be as inhibitors of numerous enzymes such as DNA synthetases and RNA polymerases, they have been reported to present an excellent inhibition of human immunodeficiency virus (HIV-1) Protease (PR) and Reverse Transcriptase (RT) [8]
Molecular Modeling In order to gain insight into the interaction modes of the studied flavones, the frontier orbitals HOMO and LUMO were used to measures the electron donor character and acceptor, this energy is represented in the (Figure 3), The molecular orbital shows that the contribution of HOMO is especially located on the core B comprising the sulfonyle group (Sulfonate) in position 5’ which is responsible for electron transfer between molecules and target key residue in the HIV1-RT
Summary
Flavones are a subclass of natural compounds belonging to the class of flavonoids which are secondary metabolites very common in plant kingdom and responsible for numerous biological activities. Previous research showed that the mechanism of action of flavones are related to their ability to scavenge free radicals and to complexing essential metals for the catalytic activity of enzymes [5, 6]. Previous studies have shown that some methoxylated flavones in position 3 have significant antiviral activities [9], citing for example the 4’,7dihydroxy -3,5,6-timethoxyflavone tested in vitro have a significant antiviral activity against the poliovirus type 1 and rhinavirus type 15 [10], on the other hand, studies have shown that flavonoids carrying numerous hydroxyl groups, especially in position 5’ and 4’ (Apigenin, Myricetine...), exhibit very significant inhibitory activities for HIV1-RT with IC50 values less than 100 μg/mL [11], the baïcalein (5,6,7-trihydroxyflavone) tested on the HIV-1 RT exhibited a 90% inhibition of the enzyme at a concentration of 2μg/ml [12]. The xanthohumol, a flavonoid extracted from Humulus lupulus, was tested for its HIV-1 RT inhibitory activity by the Yong-Tang Zheng et al, the results showed a significant inhibitory potency at concentrations of approximately 24 μM [14]
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