Perceiving SARS-CoV-2 Mpro and PLpro dual inhibitors from pool of recognized antiviral compounds of endophytic microbes: an in silico simulation study

Abstract

Coronavirus disease 2019 (COVID-19) persists and shook the global population where the endgame to this pandemic is brought on by developing vaccines in record-breaking time. Nevertheless, these vaccines are far from perfect where their efficiency ranges from 65 to 90%; therefore, vaccines are not the one only solution to overcome this situation, and apart from administration of vaccines, the scientific community is at quest for finding alternative solutions to incumber SARS-CoV-2 infection. In this study, our research group is keen on identifying a bioactive molecule that is independent in its mode of action from existing vaccines which can potentially target the SARS-CoV-2 virus replicative efficacy. Papain-like protease (PLpro) and main protease (Mpro) are the most lucrative targets of COVIDs against which the drugs can be developed, as these proteases play a vital role in the replication and development of viral particles. Researchers have modelled a compound such as GRL0617 and X77 as an inhibitor of Mpro and PLpro, respectively, but use of these compounds has several limitations on hosts like toxicity and solubility. Under the current study by deploying rigorous computational assessments, pool of microbial secondary metabolites was screened and handpicked to search a structural or functional analogue of GRL0617 and X77, with an idea to identify a compound that can serve as dual inhibitor for both PLpro and Mpro. From the manually curated database of known antiviral compounds from fungal origin, we found cytonic acids A and B to potentially serve as dual inhibitor of PLpro and Mpro.

SARS-CoV-2 proteases Mpro and PLpro: Design of inhibitors with predicted high potency and low mammalian toxicity using artificial neural networks, ligand-protein docking, molecular dynamics simulations, and ADMET calculations

“…Apart from the global similarities among the RMSF profiles of the complexes, it is important to focus on the ligand RMSF because it would be desirable to select compounds with low values of this parameter [ 90 ]. The ligand RMSF values for the PLpro complexes were as follows (in descending order): 89–07 (2.58 Å) , 89–32 (1.82 Å) , 89–38 (1.76 Å) , 89–00 (1.65 Å), and GRL0617 (0.97 Å).…”

Extending the lore of curcumin as dipteran Butyrylcholine esterase (BChE) inhibitor: A holistic molecular interplay assessment

“…Computational rational drug designing and other computational approaches for developing inhibitors, drugs and alternate medicines have gained lot of attention owing to high accuracy and robustness [ 43 – 48 ]. Under current study, the top 13 phytochemicals identified using computational screening that showed probable interaction with BChE are curcumin, desmethoxycurcumin, gingerol, asarinin, capsaicin, sesamin, 6-shogaol, rosmarinic acid, piperine, hesperetin, zingiberene, betulinic acid, and ursolic acid.…”

Combining computational and experimental evidence on the activity of antimalarial drugs on papain‐like protease of SARS‐CoV‐2: A repurposing study

“…Moreover, the absence of Tyr268 in Middle East Respiratory Syndrome (MERS) PLpro caused the lack of activity of known potent inhibitors against this virus (Shin et al, 2020). Notably, Asp164, Tyr264, Tyr268, and Gln269 are among the main key residues identified in the interaction with inhibitors, as reported in recent studies (Prajapati et al, 2022;Sencanski et al, 2022;Shen et al, 2022).…”