ABSTRACT
The study aims to identify the bioactive secondary metabolites from the leaves of Papuacedrus papuana that have not been reported yet so far. Two main antibacterial compounds, ferruginol, and trans-communic acid were isolated from the leaves of the plant through several chromatography techniques, including a TLC-direct bioautography technique. The antibacterial activity of abietane and labdane diterpenes were categorized as strong. The values of MIC were 16 and 4 µg/mL for ferruginol and 8 and 16 for trans-communic acid against E. coli (InaCC B5) and S. aureus (InaCC B4), respectively. In addition, only ferruginol showed a moderate antioxidant activity with an IC50 value of 116.12 μg/mL. By docking studies, both compounds showed their more stable interaction with structural SARS-CoV-2 proteins, i.e., 6vxx Spike glycoprotein and 6m0j spike receptor compared to non-structural proteins such as 3CLpro, Mpro, and RdRp proteases. © 2022, Rasayan Journal of Chemistry, c/o Dr. Pratima Sharma. All rights reserved.
ABSTRACT
The emergence of the global pandemic COVID-19 lead to a huge demand for the therapeutic agent to combat the disease. Since the FDA approval of some of HIV-1 main protease inhibitors such as ritonavir lopinavir to treat COVID-19, the investigation of anti-HIV inhibitor to inhibit SARS-CoV-2 main protease (Mpro) is getting considerably much attention. This study evaluates the potency of sixteen selected natural flavonoids which were previously reported active to block HIV-1 protease as potential inhibitors of SARS-CoV-2 Mpro. The molecular docking and dynamic study were completed to know the binding affinity and stability of the protein-ligand complex via docking study along with molecular dynamic simulations. Moreover, drug-likeness was also evaluated through via ADMET evaluation. This study revealed robinin (6), a flavonol molecule with linked to galactose-rhamnose at C3 and rhamnose molecule at C7, exhibited the highest binding affinity (-9 kcal/mol) among others. The amino acids that interacted with robinin were Asn142;Gly143;Arg188;Thr190. The binding affinity of robinin surpassed the binding affinity of ritonavir (-7.7 kcal/mol) and lopinavir (-8.2 kcal/mol). The replacement of the hydroxyl group from the flavonoid skeleton at C-7, C-4' was proposed to affect the binding affinity. The free hydroxyl group particularly in A ring and the position of the hydroxyl group were important to improve the binding affinity. The molecular dynamic simulation showed the stability of Mpro-robinin during the simulation period. The ADME evaluation referring to Lipinski's rule of 5 revealed that the flavonoids (2,5,6,9,10,13,14,15) show low oral bioavailability and absorption. Robinin exhibited a good drug-likeness score (value:1) with an unconcerned level of acute toxicity. From this study, it was concluded that robinin showed the most potent natural flavonoids studied to inhibit SASR-CoV-2 Mpro by both docking study and ADME/tox properties evaluation.