Antiviral activities of natural compounds and ionic liquids to inhibit the Mpro of SARS-CoV-2: a computational approach

The recalcitrant spread of the COVID-19 pandemic produced by the novel coronavirus SARS-CoV-2 is one of the most destructive occurrences in history. Despite the availability of several effective vaccinations and their widespread use, this line of immunization often faces questions about its long-term efficacy. Since coronaviruses rapidly change, and multiple SARS-CoV-2 variants have emerged around the world. Therefore, finding a new target-based medication became a priority to prevent and control COVID-19 infections. The main protease (Mpro) is a salient enzyme in coronaviruses that plays a vital role in viral replication, making it a fascinating therapeutic target for SARS-CoV-2. We screened 0.2 million natural products against the Mpro of SARS-CoV-2 using the Universal Natural Product Database (UNPD). As well, we studied the role of ionic liquids (ILs) on the structural stabilization of Mpro. Cholinium-based ILs are biocompatible and used for a variety of biomedical applications. Molecular docking was employed for the initial screening of natural products and ILs against Mpro. To predict the drug-likeness features of lead compounds, we calculated the ADMET properties. We performed MD simulations for the selected complexes based on the docking outcomes. Using MM/PBSA approaches, we conclude that compounds NP-Hit2 (−25.6 kcal mol⁻¹) and NP-Hit3 (−25.3 kcal mol⁻¹) show stronger binding affinity with Mpro. The hotspot residues of Thr25, Leu27, His41, Met49, Cys145, Met165, and Gln189 strongly interacted with the natural compounds. Furthermore, naproxenate, ketoprofenate, and geranate, cholinium-based ILs strongly interact with Mpro and these ILs have antimicrobial properties. Our findings will aid in the development of effective Mpro inhibitors.

The selected natural compounds NP-Hit2, NP-Hit3 and cholinium-based ILs exhibit potential antiviral activity against Mpro of SARS-CoV-2.     

Assessment of the antioxidant potential of Pergularia daemia (Forsk.) extract in vitro and in vivo experiments on hamster buccal pouch carcinogenesis

ObjectiveThe aim of the present study was to investigate the in vitro antioxidant assays and in vivo non enzymatic antioxidant potential of aerial parts of Pergularia daemia methanolic extract (PDME) on 7, 12-dimethylbenz(a)anthracene (DMBA) induced hamster buccal pouch (HBP) carcinogenesis.MethodsThe plant extract was tested for their total phenol and flavonoid content and radical scavenging effect such as 2, 2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS^?₊) radical decolorization assay, DPPH (2, 2-diphenyl, 2-picryl hydrazyl) radical scavenging, nitric oxide radical scavenging, reducing power assays.ResultsAccording to IC₅₀values obtained, PDME contains more powerful antioxidant compounds than gallic acid. The level of plasma vitamin C and the levels of Vitamin E and GSH in the plasma and erythrocyte lysate were decreased while the buccal tissue levels of vitamin E and GSH were increased in DMBA induced animals. Pretreatment with P.daemia (200 mg/kg bw) to DMBA induced animals significantly (P < 0.05) increased the levels of plasma and erythrocyte vitamin C, vitamin E and GSH where as the levels of vitamin E and GSH in the buccal tissue were increased compared to DMBA alone induced animals.ConclusionsThe PDME exhibited strong antioxidant activity in free radical scavenging assays and hamster buccal pouch carcinogenesis.     

Down regulation of lactate dehydrogenase initiates apoptosis in HeLa and MCF-7 cancer cells through increased voltage-dependent anion channel protein and inhibition of BCL2

Malignant cells commonly use aerobic glycolysis for ATP production; this is known as the Warburg effect, where pyruvate is converted to lactate, by enzyme lactate dehydrogenase A (LDH-A). In this study, we have investigated the effect of inhibition of LDH-A on cells viability and identifying the mechanism of cell death in HeLa and MCF-7 cancer cells.Human cervical cancer HeLa cell line and breast cancer MCF-7 cell line were used to investigate the effect of inhibition of LDH-A by sodium oxamate on cell survival and proliferation using western blot, spectrophotometry, and immunofluorescent study.There was significant reduction in LDH-A (P < 0.001) and cell viability (P < 0.001) in a dose-dependent mode in both HeLa and MCF-7 SO-treated cancer cells. The voltage-dependent anion channel (VDAC) protein was significantly increased (P < 0.001) in association with decreased LDH-A. The proapoptotic proteins; cytochrome C (P < 0.001), BAX (P < 0.001), cleaved caspase-3 (P < 0.001), cleaved caspase-8 (P < 0.001), and cleaved caspase-9 (P < 0.001) were significantly increased in association with decreased LDH-A. While, the anti-apoptotic protein Bcl2 was significantly decreased (P < 0.001) in association with decreased LDH-A.We conclude that Inhibition of LDH-A can decrease cells viability through activation of intrinsic apoptotic pathway via increased VDAC protein and inhibition of Bcl2 as well as activation of the extrinsic apoptotic pathway through activation of caspase-8.