Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly infectious zoonotic virus first reported into the human population in September 2012 on the Arabian Peninsula. The virus causes severe and often lethal respiratory illness in humans with an unusually high fatality rate. The N-terminal domain (NTD) of receptor-binding S1 subunit of coronavirus spike (S) proteins can recognize a variety of host protein and mediates entry into human host cells. Blocking the entry by targeting the S1-NTD of the virus can facilitate the development of effective antiviral drug candidates against the pathogen. Therefore, the study has been designed to identify effective antiviral drug candidates against the MERS-CoV by targeting S1-NTD. Initially, a structure-based pharmacophore model (SBPM) to the active site (AS) cavity of the S1-NTD has been generated, followed by pharmacophore-based virtual screening of 11,295 natural compounds. Hits generated through the pharmacophore-based virtual screening have re-ranked by molecular docking and further evaluated through the ADMET properties. The compounds with the best ADME and toxicity properties have been retrieved, and a quantum mechanical (QM) based density-functional theory (DFT) has been performed to optimize the geometry of the selected compounds. Three optimized natural compounds, namely Taiwanhomoflavone B (Amb23604132), 2,3-Dihydrohinokiflavone (Amb23604659), and Sophoricoside (Amb1153724), have exhibited substantial docking energy >−9.00 kcal/mol, where analysis of frontier molecular orbital (FMO) theory found the low chemical reactivity correspondence to the bioactivity of the compounds. Molecular dynamics (MD) simulation confirmed the stability of the selected natural compound to the binding site of the protein. Additionally, molecular mechanics generalized born surface area (MM/GBSA) predicted the good value of binding free energies (ΔG bind) of the compounds to the desired protein. Convincingly, all the results support the potentiality of the selected compounds as natural antiviral candidates against the MERS-CoV S1-NTD.

The local medicinal plant Rhazya stricta Decne is reviewed for its folkloric medicinal, phytochemical, pharmacological, biological, and toxicological features. R. stricta has been used widely in different cultures for various medical disorders. The phytochemical studies performed on the R. stricta extract revealed many alkaloidal and fatty acid compounds. Moreover, several flavonoid and terpenoid compounds were also detected. Pharmacological activates of R. stricta extracts are approved to possess antimicrobial, antioxidant, anticancer, antidiabetic, and antihypertensive activities. Additionally, R. stricta extract was found to hold biological activates such as larvicidal and phytoremediation activates R. stricta extract was found to be toxic, genotoxic, and mutagenic. R. stricta contains novel phytochemical compounds that have not been investigated pharmacologically. Further research is needed through in vitro and in vivo experiments to pave the road for these compounds for medical, veterinary, and ecological uses.

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The recent emerging SARS-CoV-2 pandemic which was identified as COVID-19 disease has become a global health concern. It resulted in a major pneumonia outbreak worldwide. Currently, there are no approved drugs and several attempts have been made to use computational program approaches in drug repurposing for COVID-19 treatment. The SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) is vital for binding to the hACE2 receptor, which initiates entry into human cells, and thus is a key target for antiviral compound development. Many herbal natural products have been proved to exert virucidal activity against the vast majority of pathogenic viruses. Rhazya stricta, a folkloric medicinal desert plant of Saudi Arabia was shown to exhibit bactericidal activity against a verity of pathogens including Methicillin-resistant Staphylococcus aureus (MRSA) and some other Multidrug-Resistant Organisms (MDR’s). This study aims to test for antiviral activity of the folkloric medicinal desert plant Rhazya stricta against coronavirus SARS-CoV-2. We identified three non-alkaloid herbal natural compounds Lig230, Lig434, and Lig68 from Rhazya Stricta that bind and interact significantly with RBD (PDB: I.D. 6M0J) by using virtual screening and computer aiding program Autodock vina. Based on the results of docking scores, molecular docking simulations, RMSD, RMSF, and radius of gyration (Rg), the virtually screened antiviral compounds showed good binding interactions and high stability. Lig230 revealed the highest average of interaction energy during MD simulation (− 417.284 kJ/mol) followed by Lig434 (− 366.186 kJ/mol) and the lowest interaction energy was by Lig68 (− 352.5872 kJ/mol). To evaluate the oral bioavailability, a drug-likeness profile was performed by SwissADME and the results revealed that these compounds expected to confront permeability and solubility difficulties if they were introduced orally. In conclusion, the suggested three compounds can serve as potential anti- SARS-CoV-2 and should be furtherly tested in vitro and in vivo.

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The latest coronavirus pandemic (SARS-CoV-2) poses an exceptional threat to human health and society worldwide. The coronavirus (SARS-CoV-2) spike (S) protein, which is required for viral–host cell penetration, might be considered a promising and suitable target for treatment. In this study, we utilized the nonalkaloid fraction of the medicinal plant Rhazya stricta to computationally investigate its antiviral activity against SARS-CoV-2. Molecular docking and molecular dynamics simulations were the main tools used to examine the binding interactions of the compounds isolated by HPLC analysis. Ceftazidime was utilized as a reference control, which showed high potency against the SARS-CoV-2 receptor binding domain (RBD) in an in vitro study. The five compounds (CID:1, CID:2, CID:3, CID:4, and CID:5) exhibited remarkable binding affinities (CID:1, − 8.9; CID:2, − 8.7; and CID:3, 4, and 5, − 8.5 kcal/mol) compared to the control compound (− 6.2 kcal/mol). MD simulations over a period of 200 ns further corroborated that certain interactions occurred with the five compounds and the nonalkaloidal compounds retained their positions within the RBD active site. CID:2, CID:4, and CID:5 demonstrated high stability and less variance, while CID:1 and CID:3 were less stable than ceftazidime. The average number of hydrogen bonds formed per timeframe by CID:1, CID:2, CID:3, and CID:5 (0.914, 0.451, 1.566, and 1.755, respectively) were greater than that formed by ceftazidime (0.317). The total binding free energy calculations revealed that the five compounds interacted more strongly within RBD residues (CID:1 = − 68.8, CID:2 = − 71.6, CID:3 = − 74.9, CID:4 = − 75.4, CID:5 = − 60.9 kJ/mol) than ceftazidime (− 34.5 kJ/mol). The drug-like properties of the selected compounds were relatively similar to those of ceftazidime, and the toxicity predictions categorized these compounds into less toxic classes. Structural similarity and functional group analyses suggested that the presence of more H-acceptor atoms, electronegative atoms, acidic oxygen groups, and nitrogen atoms in amide or aromatic groups were common among the compounds with the lowest binding affinities. In conclusion, this in silico work predicts for the first time the potential of using five R. stricta nonalkaloid compounds as a treatment strategy to control SARS-CoV-2 viral entry.

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