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Natural products have been included in our dietary supplements and have been shown to have numerous therapeutic properties. With the looming danger of many zoonotic agents and novel emerging pathogens mainly of viral origin, many researchers are launching various clinical trials, testing these compounds for their antiviral activity. The present work deals with some of the available natural compounds from the literature that have demonstrated activity in counteracting pathogen infections. Accordingly, we screened, using in silico methods, this subset of natural compounds for searching potential drug candidates able to interfere in the recognition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and its target human angiotensin-converting enzyme 2 ( h ACE2) receptor, leading to the viral entry. Disrupting that recognition is crucial for slowing down the entrance of viral particles into host cells. The selected group of natural products was examined, and their interaction profiles against the host cell target protein ACE2 were studied at the atomic level. Based on different computer-based procedures including molecular docking, physicochemical property evaluation, and molecular dynamics, butein was identified as a potential hit molecule able to bind the h ACE2 receptor. The results indicate that herbal compounds can be effective for providing possible therapeutics for treating and managing coronavirus disease 2019 (COVID-19) infection. Graphical abstract

: Outbreaks due to Severe Acute Respiratory Syndrome-Corona virus 2 (SARS-CoV-2) initiated in Wuhan city, China, in December 2019 which continued to spread internationally, posing a pandemic threat as declared by WHO and as of March 10, 2021, confirmed cases reached 118 million along with 2.6 million deaths worldwide. In the absence of specific antiviral medication, symptomatic treatment and physical isolation remain the options to control the contagion. The recent clinical trials on antiviral drugs highlighted some promising compounds such as umifenovir (haemagglutinin-mediated fusion inhibitor), remdesivir (RdRp nucleoside inhibitor), and favipiravir (RdRp Inhibitor). WHO launched a multinational clinical trial on several promising analogs as a potential treatment to combat SARS infection. This situation urges a holistic approach to invent safe and specific drugs as a prophylactic and therapeutic cure for SARS-related-viral diseases, including COVID-19. : It is significant to note that researchers worldwide have been doing their best to handle the crisis and have produced an extensive and promising literature body. It opens a scope and allows understanding the viral entry at the molecular level. A structure-based approach can reveal the molecular-level understanding of viral entry interaction. The ligand profiling and non-covalent interactions among participating amino-acid residues are critical information to delineate a structural interpretation. The structural investigation of SARS virus entry into host cells will reveal the possible strategy for designing drugs like entry inhibitors. : The structure-based approach demonstrates details at the 3D molecular level. It shows specificity about SARS-CoV-2 spike interaction, which uses human angiotensin-converting enzyme 2 (ACE2) as a receptor for entry, and the human protease completes the process of viral fusion and infection. : The 3D structural studies reveal the existence of two units, namely S1 and S2. S1 is called a receptor-binding domain (RBD) and responsible for interacting with the host (ACE2), and the S2 unit participates in the fusion of viral and cellular membranes. TMPRSS2 mediates the cleavage at S1/S2 subunit interface in S-protein of SARS CoV-2, leading to viral fusion. Conformational difference associated with S1 binding alters ACE2 interaction and inhibits viral fusion. Overall, the detailed 3D structural studies help understand the 3D structural basis of interaction between viruses with host factors and available scope for the new drug discovery process targeting SARS-related virus entry into the host cell.