In silico drug discovery of major metabolites from spices as SARS-CoV-2 main protease inhibitors

Abstract

Coronavirus Disease 2019 (COVID-19) is an infectious illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), originally identified in Wuhan, China (December 2019) and has since expanded into a pandemic. Here, we investigate metabolites present in several common spices as possible inhibitors of COVID-19. Specifically, 32 compounds isolated from 14 cooking seasonings were examined as inhibitors for SARS-CoV-2 main protease (M pro ), which is required for viral multiplication. Using a drug discovery approach to identify possible antiviral leads, in silico molecular docking studies were performed. Docking calculations revealed a high potency of salvianolic acid A and curcumin as M pro inhibitors with binding energies of −9.7 and −9.2 kcal/mol, respectively. Binding mode analysis demonstrated the ability of salvianolic acid A and curcumin to form nine and six hydrogen bonds, respectively with amino acids proximal to M pro 's active site. Stabilities and binding affinities of the two identified natural spices were calculated over 40 ns molecular dynamics simulations and compared to an antiviral protease inhibitor (lopinavir). Molecular mechanics-generalized Born surface area energy calculations revealed greater salvianolic acid A affinity for the enzyme over curcumin and lopinavir with energies of −44.8, −34.2 and −34.8 kcal/mol, respectively. Using a STRING database, protein-protein interactions were identified for salvianolic acid A included the biochemical signaling genes ACE, MAPK14 and ESR1; and for curcumin, EGFR and TNF. This study establishes salvianolic acid A as an in silico natural product inhibitor against the SARS-CoV-2 main protease and provides a promising inhibitor lead for in vitro enzyme testing.

In Silico Evaluation of Prospective Anti-COVID-19 Drug Candidates as Potential SARS-CoV-2 Main Protease Inhibitors

“…Prevention of the SARS-CoV-2 replication could also be achieved by targeting the viral main protease (M pro ) (also called 3-chymotrypsin-like protease (3CL pro )) and papain-like protease (PL pro ). Because of the essential role of M pro in the viral life cycle, numerous experimental and in silico studies have attempted to identify small molecules, natural products, and repurposed drugs as potential SARS-CoV-2 M pro inhibitors [ 14 – 23 ]. Until now, the outcomes of the initiated clinical trials for protease inhibitors have not yet been released [ 18 , 24 , 25 ].…”

Screening of drug databank against WT and mutant main protease of SARS-CoV-2: Towards finding potential compound for repurposing against COVID-19

“…Salvianolic acid A, a phenolic acid extracted from sage ( Salvia officinalis ) ( Ma et al, 2019 ) was another compound demonstrating high binding affinity against all the selected Mpro mutants. This compound has also been previously reported to carry inhibitory potential against Mpro ( Ibrahim et al, 2020 ). 3,8-Diamino-6-phenyl-5-[6-[1-[2-[(1,2,3,4-tetrahydro-9-acridinyl)amino]ethyl]-1H-1,2,3-triazol-4-YL]hexyl]-phenanthridinium also known as TZ4, a widely reported inhibitor of acetylcholinesterase was also found to be very effective against the WT and all selected Mpro mutants ( Table 2 ).…”

Therapeutic Intervention of COVID-19 by Natural Products: A Population-Specific Survey Directed Approach

“…Another study utlized Schrödinger Package for pharmacophore-based virtual screening of 409,147 molecules from supernatural product (SNP) database (274,363), Zinc natural database (120,720) and MNP database (14,064) to identify SN00293542, and SN00382835 as inhibitors against 3CLpro [ 32 ]. Interestingly, Salvianolic acid A was identified against 3CLpro by screening 32 phytochemicals from 14 cooking spices utilizing molecular docking in AutoDock4.2.6 followed by molecular dynamics in AMBER16 [ 33 ]. It is plausible to utilize in silico screening with different combinations of NP secondary metabolites database, different host and/or SARS-CoV-2 receptors and software platforms (open access AutoDock and AutoDock Vina or paid package like Schrödinger) to identify more potential lead candidates from NP against SARS-CoV-2.…”