Potential inhibitors for SARS-CoV-2 Mpro from marine compounds

Preventing the biological activity of SARS-CoV-2 main protease using natural compounds is of great interest. In this context, using a combination of AutoDock Vina and fast pulling of ligand simulations, eleven marine fungi compounds were identified that probably play as highly potent inhibitors for preventing viral replication. In particular, four compounds including M15 (3-O-(6-O-α-l-arabinopyranosyl)-β-d-glucopyranosyl-1,4-dimethoxyxanthone), M8 (wailupemycins H), M11 (cottoquinazolines B), and M9 (wailupemycins I) adopted the predicted ligand-binding free energy of −9.87, −9.82, −9.62, and −9.35 kcal mol⁻¹, respectively, whereas the other adopted predicted ligand-binding free energies in the range from −8.54 to −8.94 kcal mol⁻¹. The results were obtained using a combination of Vina and FPL simulations. Notably, although, AutoDock4 adopted higher accurate results in comparison with Vina, Vina is proven to be a more suitable technique for rapidly screening ligand-binding affinity with a large database of compounds since it requires much smaller computing resources. Furthermore, FPL is better than Vina to classify inhibitors upon ROC-AUC analysis.

Preventing the biological activity of SARS-CoV-2 main protease using natural compounds is of great interest.     

Chemical constituents from Limonium tubiflorum and their in silico evaluation as potential antiviral agents against SARS-CoV-2

Wild plants growing in the Egyptian deserts are facing abiotic stress, which can lead to interesting & safe natural products possessing potential chemical profiles. Consequently, our study was designed to assess the phytochemical composition of the aerial parts of Limonium tubiflorum (family Plumbaginaceae) growing wild in Egypt for the first time. In addition, in silico screening and molecular dynamic simulation of all isolated phytoconstituents were run against the main protease (M^pro) and spike glycoprotein SARS-CoV-2 targets which displayed a crucial role in the replication of this virus. Our findings showed that the phytochemical investigation of 70% ethanol extract of L. tubiflorum aerial parts afforded six known flavonoids; myricetin 3-O-(2′′-galloyl)-β-d-galactopyranoside (1), myricetin 3-O-(2′′-galloyl)-α-l-rhamnopyranoside (2), myricetin 3-O-(3′′-galloyl)-α-l-rhamnopyranoside (3), myricetin 3-O-β-d-galactopyranoside (5), apigenin (6), myricetin (7), along with two known phenolic acid derivatives; gallic acid (4) and ethyl gallate (8). Docking studies revealed that compounds (1) & (2) were the most effective compounds with binding energies of −17.9664 & −18.6652 kcal mol⁻¹ against main protease and −18.9244 & −18.9272 kcal mol⁻¹ towards spike glycoprotein receptors, respectively. The molecular dynamics simulation experiment agreed with the docking study and reported stability of compounds (1) and (2) against the selected targets which was proved by low RMSD for the tested components. Moreover, the structure–activity relationship revealed that the presence of the galloyl moiety is necessary for enhancement of the activity. Overall, the galloyl substructure of myricetin 3-O-glycoside derivatives (1 and 2) isolated from L. tubiflorum may be a possible lead for developing COVID-19 drugs. Further, in vitro and in vivo assays are recommended to support our in silico studies.

Wild plants growing in the Egyptian deserts are facing abiotic stress, which can lead to interesting & safe natural products possessing potential chemical profiles.     

Antiproliferative activity of new pentacyclic triterpene and a saponin from Gladiolus segetum Ker-Gawl corms supported by molecular docking study

A new triterpenoidal saponin identified as 3-O-[β-d-glucopyranosyl-(1 → 2)-β-d-glucopyranosyl-(1 → 4)-β-d-xylopyranosyl]-2β,3β,16α-trihydroxyolean-12-en-23,28-dioic acid-28-O-α-l-rhamnopyranosyl-(1 → 4)-α-l-rhamnopyranosyl-(1 → 2)-β-d-glucopyranosyl-(1 → 2)-α-l-arabinopyranoside 1 together with a new oleanane triterpene identified as 2β,3β,13α,22α-tetrahydroxy olean-23,28-dioic acid 2 and 6 known compounds (3–8) have been isolated from Gladiolus segetum Ker-Gawl corms. The structural elucidation of the isolated compounds was confirmed using different chemical and spectroscopic methods, including 1D and 2D NMR experiments as well as HR-ESI-MS. Moreover, the in vitro cytotoxic activity of the fractions and that of the isolated compounds 1–8 were investigated against five human cancer cell lines (PC-3, A-549, HePG-2, MCF-7 and HCT-116) using doxorubicin as a reference drug. The results showed that the saponin fraction exhibited potent in vitro cytotoxic activity against the five human cancer cell lines, whereas the maximum activity was exhibited against the PC-3 and A-549 cell lines with the IC₅₀ values of 1.13 and 1.98 μg mL⁻¹, respectively. In addition, compound 1 exhibited potent activity against A-549 and PC-3 with the IC₅₀ values of 2.41 μg mL⁻¹ and 3.45 μg mL⁻¹, respectively. Interestingly, compound 2 showed the maximum activity against PC-3 with an IC₅₀ of 2.01 μg mL⁻¹. These biological results were in harmony with that of the molecular modeling study, which showed that the cytotoxic activity of compound 2 might occur through the inhibition of the HER-2 enzyme.

A new triterpenoidal saponin 1, a new oleanane triterpene 2, and 6 known compounds (3–8) have been isolated from Gladiolus segetum Ker-Gawl corms.     

Theoretical insights into the effect of halogenated substituent on the electronic structure and spectroscopic properties of the favipiravir tautomeric forms and its implications for the treatment of COVID-19

In this study, we systematically investigated the electronic structure, spectroscopic (nuclear magnetic resonance, infrared, Raman, electron ionization mass spectrometry, UV-Vis, circular dichroism, and emission) properties, and tautomerism of halogenated favipiravir compounds (fluorine, chlorine, and bromine) from a computational perspective. Additionally, the effects of hydration on the proton transfer mechanism of the tautomeric forms of the halogenated favipiravir compounds are discussed. Our results suggest that spectroscopic properties allow for the elucidation of such tautomeric forms. As is well-known, the favipiravir compound has excellent antiviral properties and hence was recently tested for the treatment of new coronavirus (SARS-CoV-2). Through in silico modeling, in the current study, we evaluate the role of such tautomeric forms in order to consider the effect of drug-metabolism in the inhibition process of the main protease (M^pro) and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 virus. According to the molecular docking, all halogenated compounds presented a better interaction energy than the co-crystallized active ligand (−3.5 kcal mol⁻¹) in the viral RdRp, in both wild-type (−6.3 to −6.5 kcal mol⁻¹) and variant (−5.4 to −5.6 kcal mol⁻¹) models. The variant analyzed for RdRp (Y176C) decreases the affinity of the keto form of the compounds in the active site, and prevented the ligands from interacting with RNA. These findings clearly indicated that all these compounds are promising as drug candidates for this molecular target.

In this study, we systematically investigated the electronic structure, spectroscopic properties, and tautomerism of halogenated favipiravir compounds (fluorine, chlorine, and bromine) from a computational perspective.     

In vitro and in silico studies of SARS-CoV-2 main protease Mpro inhibitors isolated from Helichrysum bracteatum

Discovering SARS-CoV-2 inhibitors from natural sources is still a target that has captured the interest of many researchers. In this study, the compounds (1–18) present in the methanolic extract of Helichrysum bracteatum were isolated, identified, and their in vitro inhibitory activities against SARS-CoV-2 main protease (M^pro) was evaluated using fluorescence resonance energy transfer assay (FRET-based assay). Based on 1D and 2D spectroscopic techniques, compounds (1–18) were identified as 24-β-ethyl-cholesta-5(6),22(23),25(26)-triene-3-ol (1), α-amyrin (2), linoleic acid (3), 24-β-ethyl-cholesta-5(6),22(23),25(26)-triene-3-O-β-d-glucoside (4), 1,3-propanediol-2-amino-1-(3′,4′-methylenedioxyphenyl) (5), (−)-(7R,8R,8′R)-acuminatolide (6), (+)-piperitol (7), 5,7,4′-trihydroxy-8,3′-dimethoxy flavanone (8), 5,7,4′-trihydroxy-6-methoxy flavanone (9), 4′,5-dihydroxy-3′,7,8-trimethoxyflavone (10), 5,7-dihydroxy-3′,4′,5′,8-tetramethoxy flavone (11), 1,3-propanediol-2-amino-1-(4′-hydroxy-3′-methoxyphenyl) (12), 3′,5′,5,7-tetrahydroxy-6-methoxyflavanone (13), simplexoside (piperitol-O-β-d-glucoside) (14), pinoresinol monomethyl ether-β-d-glucoside (15), orientin (16), luteolin-3′-O-β-d-glucoside (17), and 3,5-dicaffeoylquinic acid (18). Compounds 6, 12, and 14 showed comparable inhibitory activities against SARS-CoV-2 M^pro with IC₅₀ values of 0.917 ± 0.05, 0.476 ± 0.02, and 0.610 ± 0.03 μM, respectively, compared with the control lopinavir with an IC₅₀ value of 0.225 ± 0.01 μM. The other tested compounds showed considerable inhibitory activities. The molecular docking study for the tested compounds was carried out to correlate their binding modes and affinities for the SARS-CoV-2 M^pro enzyme with the in vitro results. Analyzing the results of the in vitro assay together with the obtained in silico results led to the conclusion that phenylpropanoids, lignans, and flavonoids could be considered suitable drug leads for developing anti-COVID-19 therapeutics. Moreover, the phenylpropanoid skeleton oxygenated at C3, C4 of the phenyl moiety and at C1, C3 of the propane parts constitute an essential core of the SARS-CoV-2 M^pro inhibitors, and thus could be proposed as a scaffold for the design of new anti-COVID-19 drugs.

Compounds isolated and identified from Helichrysum bracteatum leaves showed promising in vitro inhibitory activities against SARS-CoV-2 main protease (M^pro). Thus, could be considered suitable drug leads for developing anti-COVID-19 therapeutics.     

An in silico perception for newly isolated flavonoids from peach fruit as privileged avenue for a countermeasure outbreak of COVID-19

3′-Hydroxy-4′-methoxy-chroman-7-O-β-d-glucopyranoside 4 was first isolated from a natural source, together with three known compounds, the ferulic acid heptyl ester 1, naringenin 2, and 4,2′,4′-trihydroxy-6′-methoxychalcone-4′-O-β-d-glucopyranoside 3, which were isolated from peach [Prunus persica (L.) Batsch] fruits. These compounds were subjected to different virtual screening strategies in order to examine their activity to combat the COVID-19 outbreak. The study design composed of some major aspects: (a) docking with main protease (M^pro), (b) docking with spike protein, (c) 3D shape similarity study (Rapid Overlay Chemical Similarity-ROCS) to the clinically used drugs in COVID-19 patients, and finally, (d) the rule of five and the estimated pre-ADMT properties of the separated flavonoids. Docking study with M^pro of SARS-CoV-2 (PDB ID:6LU7, and 6Y2F) showed that compound 3, its aglycone part, and compound 4 have a strong binding mode to a protease receptor with key amino acids, especially Gln:166AA, and having a similar docking pose to co-crystalized ligands. Docking with the spike protein of SARS-CoV-2 illustrated that compounds 3 and 4 have a good binding affinity to PDB ID:6VSB through the formation of HBs with Asp:467A and Asn:422A. According to ROCS analysis, compounds 1, 3, and 4 displayed high similarities to drugs that prevent SARS-Co2 entry to the lung cells or block the inflammatory storm causing lung injury. Compounds 3 and 4 are good candidates for drug development especially because they showed predicted activity against SARS-CoV-2 through different mechanisms either by preventing genome replication or by blocking inflammatory storm that trigger lung injury. These compounds were isolated from peach fruit, and the study supports data and continues with the recommendation of peach fruits in controlling and managing COVID-19 cases.

3′-Hydroxy-4′-methoxy-chroman-7-O-β-d-glucopyranoside 4, together with three known compounds, ferulic acid heptyl ester 1, naringenin 2, and 4,2′,4′-trihydroxy-6′-methoxychalcone-4′-O-β-d-glucopyranoside 3, was isolated from peach fruits.     

GC-MS analysis of phytoconstituents from Ruellia prostrata and Senna tora and identification of potential anti-viral activity against SARS-CoV-2

SARS-CoV-2 is an etiologic agent responsible for the coronavirus disease 2019 (COVID-19) pandemic. The virus has rapidly extended globally and taken millions of lives due to the unavailability of therapeutics candidates against the virus. Till now, no specific drug candidates have been developed that can prevent or treat infections caused by the pathogen. The main protease (M^pro) of the SARS-CoV-2 plays a pivotal role in mediating viral replication and mechanistically inhibition of the protein can hinder the replication and infection process of the virus. Therefore, the study aimed to identify the natural bioactive compounds against the virus that can block the activity of the M^pro and subsequently block viral infections. Initially, a total of 96 phytochemicals from Ruellia prostrata Poir. and Senna tora (L.) Roxb. plants were identified through the gas chromatography-mass spectrometry (GC-MS) analytical method. Subsequently, the compounds were screened through molecular docking, absorption, distribution, metabolism, excretion (ADME), toxicity (T), and molecular dynamics (MD) simulation approach. The molecular docking method initially identified four molecules having a PubChem CID: 70825, CID: 25247358, CID: 54685836 and, CID: 1983 with a binding affinity ranging between −6.067 to −6.53 kcal mol⁻¹ to the active site of the target protein. All the selected compounds exhibit good pharmacokinetics and toxicity properties. Finally, the four compounds were further evaluated based on the MD simulation methods that confirmed the binding stability of the compounds to the targeted protein. The computational approaches identified the best four compounds CID: 70825, CID: 25247358, CID: 54685836 and, CID: 1983 that can be developed as a treatment option of SARS-CoV-2 disease-related complications. Although, experimental validation is suggested for further evaluation of the work.

Protease (M^pro) of SARS-CoV-2 has been identified as being able to hinder the replication process of the virus. Using GC-MS analytical methods, phytochemicals were identified from different medicinal plants that resulted in inhibitory activity of the molecules against M^pro.     

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.     

Anti-Hepatitis B Virus Activity and Metabolism of 2′,3′-Dideoxy-2′,3′-Didehydro-β-l(?)-5-Fluorocytidine

2′,3′-Dideoxy-2′,3′-didehydro-β-l(−)-5-fluorocytidine [l(−)Fd4C] was found to be at least 10 times more potent than β-l-2′,3′-dideoxy-3′-thiacytidine [l(−)SddC; also called 3TC, or lamivudine]against hepatitis B virus (HBV) in culture. Its cytotoxicity against HepG2 growth in culture was also greater than that of l(−)SddC (3TC). There was no activity of this compound against mitochondrial DNA synthesis in cells at concentrations up to 10 μM. The dynamics of recovery of virus from the medium of cells pretreated with equal drug concentrations were slower with l(−)Fd4C than with l(−)SddC (3TC). l(−)Fd4C could be metabolized to mono-, di-, and triphosphate forms. The degree of l(−)Fd4C phosphorylation to the 5′-triphosphate metabolite was higher than the degree of l(−)SddC (3TC) phosphorylation when equal extracellular concentrations of the two drugs were used. The apparent K_m of l(−)Fd4C phosphorylated metabolites formed intracellularly was higher than that for l(−)SddC (3TC). This may be due in part to a difference in the behavior of l(−)Fd4C and l(−)SddC (3TC) towards cytosolic deoxycytidine kinase. Furthermore, l(−)Fd4C 5′-triphosphate was retained longer within cells than l(−)SddC (3TC) 5′-triphosphate. l(−)Fd4C 5′-triphosphate inhibited HBV DNA polymerase in competition with dCTP with a K_i of 0.069 ± 0.015 μM. Given the antiviral potency and unique pharmacodynamic properties of l(−)Fd4C, this compound should be considered for development as an expanded-spectrum anti-HBV drug.Hepatitis B virus (HBV) infection is one of the most serious health issues in the world today (1, 3). β-l(−)-2′,3′-Dideoxy-3′-thiacytidine [l(−)SddC; also called 3TC, or lamivudine] (Fig. ​(Fig.1)1) is the first β-l(−) nucleoside analog identified by us and others to have potent activity against HBV in culture (4, 8, 12, 17). This drug exerts its action by inhibiting HBV DNA synthesis due to the preferential interaction of the l(−)SddC (3TC) 5′-triphosphate metabolite with HBV DNA polymerase (4). Unlike dideoxycytidine (ddC, or zalcitabine), a β-d(+) nucleoside analog with the natural nucleoside conformation in DNA and RNA, l(−)SddC (3TC) does not have potent activity against mitochondrial DNA (mtDNA) synthesis, which is important for maintaining the function of cells (4). Clinical trials of l(−)SddC (3TC) for the treatment of chronic HBV infection are ongoing and look promising (2, 7, 13, 16, 18, 19). Its potential value for HBV-infected patients undergoing liver transplantation is also being evaluated, since l(−)SddC (3TC) can suppress HBV DNA serum levels in these patients. However, apparent l(−)SddC (3TC)-resistant HBV emerged in some patients upon long-term treatment (13, 16, 18). The HBV-resistant genotype appears to be associated with the mutation of methionine to valine or isoleucine in the YMDD motif of HBV DNA polymerase (13, 16, 18). This mutation was previously demonstrated and could render duck HBV resistant to l(−)SddC (3TC) (11). It is not clear if this mutation alone can lead to resistance and, if so, to what degree HBV resistance to l(−)SddC (3TC) develops. Open in a separate windowFIG. 1Structures of l(−)deoxycytidine analogs.One approach to overcoming clinical drug resistance is to use higher dosages of l(−)SddC (3TC) given the therapeutic index of the compound in vitro. However, the potency of l(−)SddC (3TC) against HBV in the clinic could be a limiting factor given the dosage application. The antiviral potency is determined not only by its antiviral activity but also by the pharmacodynamic nature of its active metabolite, l(−)SddC (3TC) 5′-triphosphate, in vivo. A more potent compound with more favorable pharmacodynamic behavior of intracellularly active metabolites would be worth exploring.In the studies reported herein, we describe the anti-HBV activity, metabolism, and pharmacodynamic properties of 2′,3′-dideoxy-2′,3′-didehydro-β-l(−)-5-fluorocytidine [l(−)Fd4C](Fig. 1) in comparison with those of l(−)SddC (3TC), including its behavior toward deoxycytidine kinase and the interaction of l(−)Fd4C 5′-triphosphate with virion-associated HBV DNA polymerase. Preliminary studies of the anti-HBV and anti-human immunodeficiency virus (HIV) activities of l(−)Fd4C were previously reported by us and others (10, 15).     

In silico study of natural compounds from sesame against COVID-19 by targeting Mpro,PLpro and RdRp

Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads. Natural products as sesame were reported to exhibit potential to protect from COVID-19 disease. In our study, the total methanolic extract of Sesamum indicum L. seeds (sesame) were led to isolation of seven known compounds, five lignan; sesamin 1, sesamolin 2, pinoresinol 3, hydroxymatairesinol 6, spicatolignan 7, together with two simple phenolic compounds; ferulic acid 4 and vanillic acid 5. All isolated compounds were evaluated in silico against three important SARS-CoV-2 protein targets; main protease (M^pro), papain-like protease (PL^pro) and RNA-dependent RNA polymerase (RdRp) which possessed crucial role in replication and proliferation of the virus inside the human cell. The results revealed that compound 6 has the high affinity against the three main proteins, specially towards the SARS-CoV-2 M^pro that exceeded the currently used SARS-CoV-2 M^pro inhibitor darunavir as well as, exhibiting a similar binding energy at SARS CoV-2 PLpro when compared with the co-crystallized ligand. This activity continued to include the RdRp as it displayed a comparable docking score with remdesivir. Inferiorly, compounds 1 and 2 showed also similar triple inhibitory effect against the three main proteins while compound 7 exhibited a dual inhibitory effect against SARS CoV-2 PL^Pro and RdRp. Further molecular dynamic simulation experiments were performed to validate these docking experiments and to calculate their binding free energies (ΔGs). Compounds 1, 2, 3, 6, and 7 showed comparable binding stability inside the active site of each enzyme with ΔG values ranged from −4.9 to −8.8 kcal mol⁻¹. All the compounds were investigated for their ADME and drug likeness properties, which showed acceptable ADME properties and obeying Lipinski''s rule of five parameters. It can be concluded that the isolated compounds from sesame lignans could be an alternative source for the development of new natural leads against COVID-19.

Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads.     

Two novel oxetane containing lignans and a new megastigmane from Paronychia arabica and in silico analysis of them as prospective SARS-CoV-2 inhibitors

The chemical characterization of the extract of the aerial parts of Paronychia arabica afforded two oxetane containing lignans, paronychiarabicine A (1) and B (2), and one new megastigmane, paronychiarabicastigmane A (3), alongside a known lignan (4), eight known phenolic compounds (5–12), one known elemene sesquiterpene (13) and one steroid glycoside (14). The chemical structures of the isolated compounds were constructed based upon the HRMS, 1D, and 2D-NMR results. The absolute configurations were established via NOESY experiments as well as experimental and TDDFT-calculated electronic circular dichroism (ECD). Utilizing molecular docking, the binding scores and modes of compounds 1–3 towards the SARS-CoV-2 main protease (M^pro), papain-like protease (PL^pro), and RNA-dependent RNA polymerase (RdRp) were revealed. Compound 3 exhibited a promising docking score (−9.8 kcal mol⁻¹) against SARS-CoV-2 M^pro by forming seven hydrogen bonds inside the active site with the key amino acids. The reactome pathway enrichment analysis revealed a correlation between the inhibition of GSK3 and GSK3B genes (identified as the main targets of megastigmane treatment) and significant inhibition of SARS-CoV-1 viral replication in infected Vero E6 cells. Our results manifest a novel understanding of genes, proteins and corresponding pathways against SARS-CoV-2 infection and could facilitate the identification and characterization of novel therapeutic targets as treatments of SARS-CoV-2 infection.

The hydromethanolic extract of Paronychia arabica aerial parts afforded two oxetane containing lignans, paronychiarabicine A (1) and B (2), and one new megastigmane, paronychiarabicastigmane A (3), alongside a known secondary metabolites (4–14).     

A phytochemical-based medication search for the SARS-CoV-2 infection by molecular docking models towards spike glycoproteins and main proteases

Identifying best bioactive phytochemicals from different medicinal plants using molecular docking techniques demonstrates a potential pre-clinical compound discovery against SARS-CoV-2 viral infection. The in silico screening of bioactive phytochemicals with the two druggable targets of SARS-CoV-2 by simple precision/extra precision molecular docking methods was used to compute binding affinity at its active sites. phyllaemblicin and cinnamtannin class of phytocompounds showed a better binding affinity range (−9.0 to −8.0 kcal mol⁻¹) towards both these SARS-CoV-2 targets; the corresponding active site residues in the spike protein were predicted as: Y453, Q496, Q498, N501, Y449, Q493, G496, T500, Y505, L455, Q493, and K417; and M^pro: Q189, H164, H163, P168, H41, L167, Q192, M165, C145, Y54, M49, and Q189. Molecular dynamics simulation further established the structural and energetic stability of protein–phytocompound complexes and their interactions with their key residues supporting the molecular docking analysis. Protein–protein docking using ZDOCK and Prodigy server predicted the binding pose and affinity (−13.8 kcal mol⁻¹) of the spike glycoprotein towards the human ACE2 enzyme and also showed significant structural variations in the ACE2 recognition site upon the binding of phyllaemblicin C compound at their binding interface. The phyllaemblicin and cinnamtannin class of phytochemicals can be potential inhibitors of both the spike and M^pro proteins of SARS-CoV-2; furthermore, its pharmacology and clinical optimization would lead towards novel COVID-19 small-molecule therapy.

Identifying best bioactive phytochemicals from different medicinal plants using molecular docking techniques demonstrates a potential pre-clinical compound discovery against SARS-CoV-2 viral infection.     

Antioxidant and UV-radiation absorption activity of aaptamine derivatives – potential application for natural organic sunscreens

Antioxidant and UV absorption activities of three aaptamine derivatives including piperidine[3,2-b]demethyl(oxy)aaptamine (C1), 9-amino-2-ethoxy-8-methoxy-3H-benzo[de][1,6]naphthyridine-3-one (C2), and 2-(sec-butyl)-7,8-dimethoxybenzo[de]imidazo[4,5,1-ij][1,6]-naphthyridin-10(9H)-one (C3) were theoretically studied by density functional theory (DFT). Direct antioxidant activities of C1–C3 were firstly evaluated via their intrinsic thermochemical properties and the radical scavenging activity of the potential antioxidants with the HOO˙/HO˙ radicals via four mechanisms, including: hydrogen atom transfer (HAT), single electron transfer (SET), proton loss (PL) and radical adduct formation (RAF). Kinetic calculation reveals that HOO˙ scavenging in water occurs via HAT mechanism with C1 (k_app, 7.13 × 10⁶ M⁻¹ s⁻¹) while RAF is more dominant with C2 (k_app, 1.40 × 10⁵ M⁻¹ s⁻¹) and C3 (k_app, 2.90 × 10⁵ M⁻¹ s⁻¹). Antioxidant activity of aaptamine derivatives can be classified as C1 > C3 > C2. Indirect antioxidant properties based on Cu(i) and Cu(ii) ions chelating activity were also investigated in aqueous phase. All three studied compounds show spontaneous and favorable Cu(i) ion chelating activity with ΔG⁰ being −15.4, −13.7, and −15.7 kcal mol⁻¹, whereas ΔG⁰ for Cu(ii) chelation are −10.4, −10.8, and −2.2 kcal mol⁻¹ for C1, C2 and C3, respectively. In addition, all compounds show UVA and UVB absorption; in which the excitations are determined mostly as π–π* transition. Overall, the results suggest the potential applications of the aaptamines in pharmaceutics and cosmetics, i.e. as a sunscreen and antioxidant ingredient.

Antioxidant and UV absorption activities of three aaptamine derivatives were theoretically studied by density functional theory (DFT) and time-dependent density functional theory (TD-DFT).     

In silico identification of SARS-CoV-2 spike (S) protein–ACE2 complex inhibitors from eight Tecoma species and cultivars analyzed by LC-MS

Coronavirus (CoV) is a positive RNA genome virus causing a global panic nowadays. Tecoma is a medicinally-valuable genus in the Bignoniaceae family, with some of its species exhibiting anti-HIV activity. This encouraged us to conduct an in silico exploration of some phytocompounds in Tecoma species cultivated in Egypt, namely Tecoma capensis and its four varieties i.e. yellow, harmony, pink and red, T. grandiflora Loisel., T. radicans L., and one hybrid i.e. Tecoma × smithii W. Watson. LC/MS-based metabolite profiling of the studied Tecoma plants resulted in the dereplication of 12 compounds (1–12) belonging to different phytochemical classes viz. alkaloids, iridoids, flavonoids and fatty acid esters. The in silico inhibitory action of these compounds against SARS-CoV-2 spike protein C-terminal domain in complex with human ACE2 was assessed via molecular docking. Succinic acid decyl-3-oxobut-2-yl ester (10), a fatty acid ester, possessed the best binding affinity (−6.77 kcal mol⁻¹), as compared to hesperidin (13) (−7.10 kcal mol⁻¹).

In silico exploration of 12 Tecoma phytocompounds that could serve as potential inhibitors of SARS-CoV entry to host cells.     

β-Blockers bearing hydroxyethylamine and hydroxyethylene as potential SARS-CoV-2 Mpro inhibitors: rational based design,in silico,in vitro,and SAR studies for lead optimization

The global COVID-19 pandemic became more threatening especially after the introduction of the second and third waves with the current large expectations for a fourth one as well. This urged scientists to rapidly develop a new effective therapy to combat SARS-CoV-2. Based on the structures of β-adrenergic blockers having the same hydroxyethylamine and hydroxyethylene moieties present in the HIV-1 protease inhibitors which were found previously to inhibit the replication of SARS-CoV, we suggested that they may decrease the SARS-CoV-2 entry into the host cell through their ability to decrease the activity of RAAS and ACE2 as well. Herein, molecular docking of twenty FDA-approved β-blockers was performed targeting SARS-CoV-2 Mpro. Results showed promising inhibitory activities especially for Carvedilol (CAR) and Nebivolol (NEB) members. Moreover, these two drugs together with Bisoprolol (BIS) as an example from the lower active ones were subjected to molecular dynamics simulations at 100 ns. Great stability across the whole 100 ns timeframe was observed for the top docked ligands, CAR and NEB, over BIS. Conformational analysis of the examined drugs and hydrogen bond investigation with the pocket''s crucial residues confirm the great affinity and confinement of CAR and NEB within the Mpro binding site. Moreover, the binding-free energy analysis and residue-wise contribution analysis highlight the nature of ligand–protein interaction and provide guidance for lead development and optimization. Furthermore, the examined three drugs were tested for their in vitro inhibitory activities towards SARS-CoV-2. It is worth mentioning that NEB achieved the most potential anti-SARS-CoV-2 activity with an IC₅₀ value of 0.030 μg ml⁻¹. Besides, CAR was found to have a promising inhibitory activity with an IC₅₀ of 0.350 μg ml⁻¹. Also, the IC₅₀ value of BIS was found to be as low as 15.917 μg ml⁻¹. Finally, the SARS-CoV-2 Mpro assay was performed to evaluate and confirm the inhibitory effects of the tested compounds (BIS, CAR, and NEB) towards the SARS-CoV-2 Mpro enzyme. The obtained results showed very promising SARS-CoV-2 Mpro inhibitory activities of BIS, CAR, and NEB (IC₅₀ = 118.50, 204.60, and 60.20 μg ml⁻¹, respectively) compared to lopinavir (IC₅₀ = 73.68 μg ml⁻¹) as a reference standard.

Hydroxyethylamine and hydroxyethylene moieties of β-blockers exert potential SARS-CoV-2 inhibitory effects: rational-based design and in silico, in vitro, and SAR Studies.     

Chemical constituents from Carica papaya Linn. leaves as potential cytotoxic,EGFRwt and aromatase (CYP19A) inhibitors; a study supported by molecular docking

The phytochemical investigation of the hydromethanolic extract of Carica papaya Linn. leaves (Caricaceae) resulted in the isolation and characterization of ten compounds, namely; carpaine (1), methyl gallate (2), loliolide (3), rutin (4), clitorin (5), kaempferol-3-O-neohesperidoside (6), isoquercetin (7), nicotiflorin (8) and isorhamnetin-3-O-β-d-glucopyranoside (9). The compounds 2, 3, 5–7 and 9 were isolated for the first time from the genus Carica. An in vitro breast cancer cytotoxicity study was evaluated with an MCF-7 cell line using the MTT assay. Methyl gallate and clitorin demonstrated the most potent cytotoxic activities with an IC₅₀ of 1.11 ± 0.06 and 2.47 ± 0.14 μM, respectively. Moreover, methyl gallate and nicotiflorin exhibited potential EGFR^wt kinase inhibition activities with an IC₅₀ of 37.3 ± 1.9 and 41.08 ± 2.1 nM, respectively, compared with the positive control erlotinib (IC₅₀ = 35.94 ± 1.8 nM). On the other hand, clitorin and nicotiflorin displayed the strongest aromatase kinase inhibition activities with an IC₅₀ of 77.41 ± 4.53 and 92.84 ± 5.44 nM, respectively. Clitorin was comparable to the efficacy of the standard drug letrozole (IC₅₀ = 77.72 ± 4.55). Additionally, molecular docking simulations of the isolated compounds to EGFR and human placental aromatase cytochrome P450 (CYP19A1) were evaluated. Methyl gallate linked with the EGFR receptor through hydrogen bonding with a pose score of −4.5287 kcal mol⁻¹ and RMSD value of 1.69 Å. Clitorin showed the strongest interaction with aromatase (CYP19A1) for the breast cancer receptor with a posing score of −14.2074 and RMSD value of 1.56 Å. Compounds (1–3) possessed a good bioavailability score with a 0.55 value.

The phytochemical investigation of the hydromethanolic extract of Carica papaya Linn. leaves (Caricaceae) resulted in the isolation and characterization of ten compounds.     

Potential role of medicinal plants and their constituents in the mitigation of SARS-CoV-2: identifying related therapeutic targets using network pharmacology and molecular docking analyses

Since the outbreak of Coronavirus disease (COVID-19) caused by SARS-CoV-2 in December 2019, there has been no vaccine or specific antiviral medication for treatment of the infection where supportive care and prevention of complications is the current management strategy. In this work, the potential use of medicinal plants and more than 16 500 of their constituents was investigated within two suggested therapeutic strategies in the fight against SARS-CoV-2 including prevention of SARS-CoV-2 RNA synthesis and replication, through targeting vital proteins and enzymes as well as modulation of the host''s immunity through production of virulence factors. Molecular docking studies on the viral enzymes 3Clpro, PLpro and RdRp suggested rocymosin B, verbascoside, rutin, caftaric acid, luteolin 7-rutinoside, fenugreekine and cyanidin 3-(6′′-malonylglucoside) as promising molecules for further drug development. Meanwhile, the medicinal plants Glycyrrhiza glabra, Hibiscus sabdariffa, Cichorium intybus, Chrysanthemum coronarium, Nigella sativa, Anastatica hierochuntica, Euphorbia species, Psidium guajava and Epilobium hirsutum were enriched in compounds with the multi-targets PTGS2, IL2, IL1b, VCAM1 and TNF such as quercetin, ursolic acid, kaempferol, isorhamnetin, luteolin, glycerrhizin and apigenin. Enriched pathways of the molecular targets included cytokine–cytokine receptor interaction, TNF signaling pathway, NOD-like receptor signaling pathway, Toll-like receptor signaling pathway, NF-kappa B signaling pathway and JAK-STAT3 signaling pathway which are all closely related to inflammatory, innate and adaptive immune responses. The present study identified natural compounds targeting SARS-CoV-2 for further in vitro and in vivo studies and emphasizes the potential role of medicinal plants in the mitigation of SARS-CoV-2.

Since the outbreak of Coronavirus disease (COVID-19) caused by SARS-CoV-2 in December 2019, there has been no vaccine or specific antiviral medication for treatment of the infection where supportive care and prevention of complications is the current management strategy.     

Lipid polymer hybrid nanocarriers as a combinatory platform for different anti-SARS-CoV-2 drugs supported by computational studies

The COVID-19 pandemic caused by SARS-CoV-2 has demonstrated the potential of emergent pathogens to severely damage public health and global economies. As a consequence of the pandemic, millions of people have been forced into self-isolation, which has negatively affected the global economy. More efforts are needed to find new innovative approaches that could fundamentally change our understanding and management of this disaster. Herein, lipid polymer hybrid nanoparticles (LPH NPs) were utilized as a platform for the delivery of azithromycin or niclosamide in combination with piroxicam. The obtained systems were successfully loaded with both azithromycin and piroxicam (LPH_Azi–Pir) with entrapment efficiencies (EE%) of 74.23 ± 8.14% and 51.52 ± 5.45%, respectively, or niclosamide and piroxicam (LPH_Nic–Pir) with respective EE% of 85.14 ± 3.47% and 48.75 ± 4.77%. The prepared LPH NPs had a core–shell nanostructure with particle size ≈ 125 nm and zeta potential ≈ −16.5 irrespective of drug payload. A dose-dependent cellular uptake of both LPH NPs was observed in human lung fibroblast cells. An enhanced in vitro antiviral efficacy of both LPH_Azi–Pir and LPH_Nic–Pir was obtained over the mixed solution of the drugs. The LPH NPs of azithromycin or niclosamide with piroxicam displyed a promising capability to hinder the replication of SARS-CoV-2, with IC₅₀ of 3.16 and 1.86 μM, respectively. These results provide a rationale for further in vivo pharmacological as well as toxicological studies to evaluate the potential activity of these drugs to combat the COVID-19 outbreak, especially the concept of combination therapy. Additionally, the molecular docking of macrolide bioactive compounds against papain-like protease (PDB ID:6wuu) was achieved. A ligand-based study, especially rapid overlay chemical structure (ROCS), was also examined to identify the general pharmacophoric features of these compounds and their similarity to reported anti-SARS-CoV-2 drugs. Molecular dynamic simulation was also implemented.

Drug repurposing approach to combat SARS-CoV-2: lipid polymer hybrid nanoparticles (LPH) for the delivery of azithromycin or niclosamide in combination with piroxicam.     

Dalpulapans A–E from the roots of Dalbergia stipulacea

Five new compounds, dalpulapans A–E (1–5), were isolated from the hexane extract of the roots of Dalbergia stipulacea Roxb. Five new compounds, dalpulapans A–E (1–5), were isolated from the hexane extract of the roots of Dalbergia stipulacea Roxb. An evaluation of cytotoxic activity against HeLa, A549 and normal cell lines using MTT assay was performed. The results showed that R,R-velucarpin A (6) was the most active against HeLa cells with an IC₅₀ value of 10.9 ± 0.42 μM, while fortunately this compound exhibited weak cytotoxicity against normal cells (29.20 ± 1.16 μM). Structures of all isolates were identified from their 1D and 2D NMR spectroscopic data and MS analysis. Experimental and calculated ECD spectra were studied to define the absolute configurations.

Five new compounds, dalpulapans A–E (1–5), were isolated from the hexane extract of the roots of Dalbergia stipulacea Roxb.