Structure-based drug designing for potential antiviral activity of selected natural products from Ayurveda against SARS-CoV-2 spike glycoprotein and its cellular receptor

Abstract

The recent outbreak of COVID-19 caused by SARS-CoV-2 brought a great global public health and economic concern. SARS-CoV-2 is an enveloped RNA virus, from the genus Betacoronavirus. Although few molecules have been tested and shown some efficacy against SARS-CoV-2 in humans but a safe and cost-effective attachment inhibitors are still required for the treatment of COVID-19. Natural products are gaining attention because of the large therapeutic window and potent antiviral, immunomodulatory, anti-inflammatory, and antioxidant properties. Therefore, this study was planned to screen natural products from Ayurveda that have the potential to modulate host immune system as well as block the virus entry in host cells by interfering its interaction with cellular receptor and may be used to develop an effective and broad-spectrum strategy for the management of COVID-19 as well as other coronavirus infections in coming future. To decipher the antiviral activity of the selected natural products, molecular docking was performed. Further, the drug-likeness, pharmacokinetics and toxicity parameters of the selected natural products were determined. Docking results suggest that curcumin and nimbin exhibits highest interaction with spike glycoprotein (MolDock score -141.36 and -148.621 kcal/mole) and ACE2 receptor (MolDock score -142.647 and -140.108 kcal/mole) as compared with other selected natural products/drugs and controls. Also, the pharmacokinetics data illustrated that all selected natural products have better pharmacological properties (low molecular weight; no violation of Lipinski rule of five, good absorption profiles, oral bioavailability, good bloodbrain barrier penetration, and low toxicity risk). Our study exhibited that curcumin, nimbin, withaferin A, piperine, mangiferin, thebaine, berberine, and andrographolide have significant binding affinity towards spike glycoprotein of SARS-CoV-2 and ACE2 receptor and may be useful as a therapeutic and/or prophylactic agent for restricting viral attachment to the host cells. However, few other natural products like resveratrol, quercetin, luteolin, naringenin, zingiberene, and gallic acid has the significant binding affinity towards ACE2 receptor only and therefore may be used for ACE2-mediated attachment inhibition of SARS-CoV-2. Keywords COVID-19 Á SARS-CoV-2 Á Attachment inhibitor Á Natural products Á Ayurveda Á CAM (Complementary and Alternative Medicine) Vimal K. Maurya and Shailendra K. Saxena contributed equally to this work.

Curcumin as an Antiviral Agent

“…Curcumin has already been demonstrated to inhibit SARS-CoV-1 replication (EC 50 of >10 µM), the coronavirus which caused the 2003 epidemic [66]. Additionally, several molecular docking studies have been performed that suggest curcumin would be effective at inhibiting SARS-CoV-2 replication [67], through interacting with the spike glycoprotein and inhibiting angiotensin-converting enzyme 2 (ACE2) [68], inhibiting the viral non-structural protein Nsp15 [69], or inhibiting the main viral protease [70].…”

Repurposing of FDA approved drugs targeting Main protease MPro for SARS-CoV-2

“…As of now, there is no prominent treatment or vaccine that is reported or approved speci cally for treating Covid19 patients [25]. However scienti c community around the globe putting all efforts in research endeavors towards the advancement of remedial intercessions and researching viral drug targets [26].…”

Inhibitory Effect of Phytochemicals from Azadirachta indica A Juss. and Tinospora cordifolia (Thunb.) Miers against SARS-CoV-2 Mpro and Spike Protease- An In Silico Analysis

“…Indian medicinal plants are being used to treat viral infections, and could physically bind COVID-19 target proteins such as SARS-CoV-2 spike glycoprotein (PDB ID: 6VXX), SARS-CoV-2 spike ectodomain structure (PDB ID: 6VYB), and SARS coronavirus spike receptor-binding domain (PDB ID: 2AJF) hence, in turn, prevent COVID-19 virus binding to the host receptor ACE2 [18]. Nimbin, berberine, mangiferin of A indica showed signi cant binding a nity towards spike protein of SARS-CoV-2 and ACE2 receptor [46]. Molecules from A. indica and T. cordifolia may be useful as a prophylactic as well as therapeutic agents due to restricting viral attachment to the host cells and prevent replication of viral RNA.…”

“…Molecules-Curcumin, nimbin, withaferin A, piperine, mangiferin, thebaine, berberine, and andrographolide showed signi cant binding a nity towards spike glycoprotein of SARS-CoV-2 and ACE2 receptor. Ligands berberine and nimbin from T. cordifolia and A indica respectively were docked with Mpro (PDB 6LU7) and exhibited good a nities [46]. IL-6, TNF-a, and IFNs were found to be elevated in patients with SARS-CoV-2 and drugs which are regulators of interleukins, chemokines, and cytokines are helpful in as adjuvant in COVID 19 [42].…”