Exploring Toxins for Hunting SARS-CoV-2 Main Protease Inhibitors: Molecular Docking, Molecular Dynamics, Pharmacokinetic Properties, and Reactome Study.

Mahmoud A A Ibrahim,Mohamed-Elamir F Hegazy,Mohamed A M Atia,Peter A Sidhom,Alaa H M Abdelrahman,Muhammad Naeem Ahmed,Mahmoud E S Soliman,Othman R Alzahrani,Moustafa Sherief Moustafa,Paul W Paré,Ahmed M Shawky,Laila A Jaragh-Alhadad

doi:10.3390/ph15020153

Abstract

The main protease (Mpro) is a potential druggable target in SARS-CoV-2 replication. Herein, an in silico study was conducted to mine for Mpro inhibitors from toxin sources. A toxin and toxin-target database (T3DB) was virtually screened for inhibitor activity towards the Mpro enzyme utilizing molecular docking calculations. Promising toxins were subsequently characterized using a combination of molecular dynamics (MD) simulations and molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. According to the MM-GBSA binding energies over 200 ns MD simulations, three toxins—namely philanthotoxin (T3D2489), azaspiracid (T3D2672), and taziprinone (T3D2378)—demonstrated higher binding affinities against SARS-CoV-2 Mpro than the co-crystalized inhibitor XF7 with MM-GBSA binding energies of −58.9, −55.9, −50.1, and −43.7 kcal/mol, respectively. The molecular network analyses showed that philanthotoxin provides a ligand lead using the STRING database, which includes the biochemical top 20 signaling genes CTSB, CTSL, and CTSK. Ultimately, pathway enrichment analysis (PEA) and Reactome mining results revealed that philanthotoxin could prevent severe lung injury in COVID-19 patients through the remodeling of interleukins (IL-4 and IL-13) and the matrix metalloproteinases (MMPs). These findings have identified that philanthotoxin—a venom of the Egyptian solitary wasp—holds promise as a potential Mpro inhibitor and warrants further in vitro/in vivo validation.

Highlights

The causative factor in COVID-19 infection is Severe Acute Respiratory SyndromeCoronavirus-2 (SARS-CoV-2), a novel β-coronavirus of the positive-stranded RNA virus that results in gastrointestinal, respiratory, and neurological symptoms in humans [1,2].From December 2019, a gigantic economic epidemic has been disseminated globally because of COVID-19 disease [3,4]
The performance of the utilized in silico protocol to predict the binding mode of SARS-CoV-2 main protease (Mpro) inhibitor was evaluated
The co-crystallized (5S)-5-(3-{3-chloro-5-[(2chlorophenyl)methoxy]phenyl2-oxo[2H-[1,30 -bipyridine]]-5-yl)pyrimidine-2,4(3H,5H)dione (XF7) inhibitor was redocked against the SARS-CoV-2 Mpro, as well as the anticipated binding mode was compared to the experimental binding mode (PDB code: 7L13) [27]

Summary

Introduction

The causative factor in COVID-19 infection is Severe Acute Respiratory SyndromeCoronavirus-2 (SARS-CoV-2), a novel β-coronavirus of the positive-stranded RNA virus that results in gastrointestinal, respiratory, and neurological symptoms in humans [1,2].From December 2019, a gigantic economic epidemic has been disseminated globally because of COVID-19 disease [3,4]. The causative factor in COVID-19 infection is Severe Acute Respiratory Syndrome. Coronavirus-2 (SARS-CoV-2), a novel β-coronavirus of the positive-stranded RNA virus that results in gastrointestinal, respiratory, and neurological symptoms in humans [1,2]. From December 2019, a gigantic economic epidemic has been disseminated globally because of COVID-19 disease [3,4]. As of 29 December 2021, more than 281 million confirmed cases and over 5.4 million international deaths had been reported [5]. A small number of vaccines have currently been approved under emergency use authorization [6]. Notwithstanding the weak vaccination rate, the deficiency of specific therapies, and the development of numerous viral variants, the pandemic goes on to distribute quickly and intricately. More outstanding efforts are required to discover safe and potent drugs against SARS-CoV-2

Methods

Results

Conclusion