We examined the effect of Niemann-Pick disease type 2 (NPC2) protein and some late endosomal lipids [sphingomyelin, ceramide and bis(monoacylglycero)phosphate (BMP)] on cholesterol transfer and membrane fusion. Of all lipid-binding proteins tested, only NPC2 transferred cholesterol at a substantial rate, with no transfer of ceramide, GM3, galactosylceramide, sulfatide, phosphatidylethanolamine, or phosphatidylserine. Cholesterol transfer was greatly stimulated by BMP, little by ceramide, and strongly inhibited by sphingomyelin. Cholesterol and ceramide were also significantly transferred in the absence of protein. This spontaneous transfer of cholesterol was greatly enhanced by ceramide, slightly by BMP, and strongly inhibited by sphingomyelin. In our transfer assay, biotinylated donor liposomes were separated from fluorescent acceptor liposomes by streptavidin-coated magnetic beads. Thus, the loss of fluorescence indicated membrane fusion. Ceramide induced spontaneous fusion of lipid vesicles even at very low concentrations, while BMP and sphingomyelin did so at about 20 mol% and 10 mol% concentrations, respectively. In addition to transfer of cholesterol, NPC2 induced membrane fusion, although less than saposin-C. In this process, BMP and ceramide had a strong and mild stimulating effect, and sphingomyelin an inhibiting effect, respectively. Note that the effects of the lipids on cholesterol transfer mediated by NPC2 were similar to their effect on membrane fusion induced by NPC2 and saposin-C.

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It is no longer news that a novel strain of coronavirus named SARS-CoV-2 is ravaging the health sector worldwide, several attempts have been made to curtail this pandemic via repurposing of old drugs but at the present, available drugs are not adequately effective. Over the year, plant phytochemicals are increasingly becoming an alternative source of an antimicrobial agent with a novel mechanism of action and limited side effects compared to synthetic drugs. Isolated saponins and tannins were evaluated for antiviral activity against SARS-CoV-2 Mpro via Molecular Docking and it was observed that a handsome number of the phytochemicals had binding affinity much better than Remdesivir, Dexamethasone, and N3 inhibitor which were used as the standard in this study. Further Investigation of drug-likeness, ADMET profile, and bioactivity of these phytochemicals revealed that binding affinity alone is not enough in the drug discovery process and that 4 hit compounds were identified as potential inhibitors of SARS-CoV-2Mpro. This preliminary study furnishes Ellagic acid, Arjunic acid, Theasapogenol B, and Euscaphic acid as potential inhibitors of SARS-CoV-2 Mpro with better pharmacokinetics and bioavailability compared to Remdesivir which is currently used compassionately.

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The continuous approval of covalent drugs in recent years for the treatment of diseases has led to an increased search for covalent agents by medicinal chemists and computational scientists worldwide. In the computational parlance, molecular docking which is a popular tool to investigate the interaction of a ligand and a protein target, does not account for the formation of covalent bond, and the increasing application of these conventional programs to covalent targets in early drug discovery practice is a matter of utmost concern. Thus, in this comprehensive review, we sought to educate the docking community about the realization of covalent docking and the existence of suitable programs to make their future virtual-screening events on covalent targets worthwhile and scientifically rational. More interestingly, we went beyond the classical description of the functionality of covalent-docking programs down to selecting the ‘best’ program to consult with during a virtual-screening campaign based on receptor class and covalent warhead chemistry. In addition, we made a highlight on how covalent docking could be achieved using random conventional docking software. And lastly, we raised an alert on the growing erroneous molecular docking practices with covalent targets. Our aim is to guide scientists in the rational docking pursuit when dealing with covalent targets, as this will reduce false-positive results and also increase the reliability of their work for translational research. Graphical abstract

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The current research used a virtual screening method to study 57 isolated phytochemicals (alkaloids, phytosterols, and flavonoids) against the SARS-CoV-2 main protease (M pro ). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the selected compounds were analysed using admetSAR tool while SwissADME and Molinspiration chemoinformatics tools were used to examine the oral bioavailability and drug-likeness properties. Parameters such as physicochemical properties, activity spectra for substances (PASS) prediction, bioactivity, binding mode, and molecular interactions were also analysed. Our results favoured Lupeol (–8.6 kcal/mol), Lupenone (–7.7 kcal/mol), Hesperetin (–7.4 kcal/mol), Apigenin (–7.3 kcal/mol) and Castasterone (–7.3 kcal/mol) as probable inhibitors of SARS-CoV-2. This is because of their good binding affinities, bioactivities, drug-likeness, ADMET properties, PASS properties, oral bioavailability, binding mode and their interactions with the active site of the target receptor compared to Remdesivir and Azithromycin. Therefore, these compounds could be explored towards the development of new therapeutic agents against SARS-CoV-2.