A Comprehensive In Silico Study of New Metabolites from Heteroxenia fuscescens with SARS-CoV-2 Inhibitory Activity.

Chemical investigation of the total extract of the Egyptian soft coral Heteroxenia fuscescens, led to the isolation of eight compounds, including two new metabolites, sesquiterpene fusceterpene A (1) and a sterol fuscesterol A (4), along with six known compounds. The structures of 1-8 were elucidated via intensive studies of their 1D, 2D-NMR, and HR-MS analyses, as well as a comparison of their spectral data with those mentioned in the literature. Subsequent comprehensive in-silico-based investigations against almost all viral proteins, including those of the new variants, e.g., Omicron, revealed the most probable target for these isolated compounds, which was found to be Mpro. Additionally, the dynamic modes of interaction of the putatively active compounds were highlighted, depending on 50-ns-long MDS. In conclusion, the structural information provided in the current investigation highlights the antiviral potential of H. fuscescens metabolites with 3ß,5α,6ß-trihydroxy steroids with different nuclei against SARS-CoV-2, including newly widespread variants.

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 (Mpro), papain-like protease (PLpro) 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 Mpro that exceeded the currently used SARS-CoV-2 Mpro 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 PLPro 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.

In silico study of natural compounds from sesame against COVID-19 by targeting Mpro, PLpro and RdRp† † Electronic supplementary information (ESI) available. See DOI: 10.1039/d1ra03937g

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 (Mpro), papain-like protease (PLpro) 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 Mpro that exceeded the currently used SARS-CoV-2 Mpro 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 PLPro 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.

Phytochemical and in silico studies for potential constituents from Centaurium spicatum as candidates against the SARS-CoV-2 main protease and RNA-dependent RNA polymerase.

In the present study, a new secoiridoid glycoside lisianthoside II 1, along with seven known compounds 2-8, were isolated from Centaurium spicatum L. In-silico molecular docking and molecular dynamic simulation against SARS-CoV-2 Main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) were conducted. The affinity docking scores revealed that 8 is the best bound ligand to Mpro active site with binding energy of -14.9877 kcal/mol (RSMD = 1.16 Å), while 6 was the highest against RdRp (-16.9572 kcal/mol, RMSD = 1.01 Å). Moreover, the molecular dynamic simulation revealed that 8 with a (ΔG) of -7.9 kcal/mol (RMSD value of 2.6 Å) and 6 (RMSD value of 1.6 Å) and binding free energy (ΔG) of -7.1 kcal/mol achieved the highest stability over 50 ns of MDS inside the Mpro and RdRp enzyme's active site, respectively. Hence, the isolated compounds could be a good lead for development of new leads targeting COVID-19.

Identification of Potential SARS-CoV-2 Main Protease and Spike Protein Inhibitors from the Genus Aloe: An In Silico Study for Drug Development.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease is a global rapidly spreading virus showing very high rates of complications and mortality. Till now, there is no effective specific treatment for the disease. Aloe is a rich source of isolated phytoconstituents that have an enormous range of biological activities. Since there are no available experimental techniques to examine these compounds for antiviral activity against SARS-CoV-2, we employed an in silico approach involving molecular docking, dynamics simulation, and binding free energy calculation using SARS-CoV-2 essential proteins as main protease and spike protein to identify lead compounds from Aloe that may help in novel drug discovery. Results retrieved from docking and molecular dynamics simulation suggested a number of promising inhibitors from Aloe. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) calculations indicated that compounds 132, 134, and 159 were the best scoring compounds against main protease, while compounds 115, 120, and 131 were the best scoring ones against spike glycoprotein. Compounds 120 and 131 were able to achieve significant stability and binding free energies during molecular dynamics simulation. In addition, the highest scoring compounds were investigated for their pharmacokinetic properties and drug-likeness. The Aloe compounds are promising active phytoconstituents for drug development for SARS-CoV-2.

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-ß-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-ß-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 (Mpro), (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 Mpro 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.