Exploring Toxins for Hunting SARS-CoV-2 Main Protease Inhibitors: Molecular Docking, Molecular Dynamics, Pharmacokinetic Properties, and Reactome Study.
Mahmoud A A IbrahimAlaa H M AbdelrahmanLaila A Jaragh-AlhadadMontaser A M Al-HammadyOthman R AlzahraniMuhammad Naeem AhmedMoustafa Sherief MoustafaMahmoud E S SolimanAhmed Mahmoud ShawkyPaul W ParéMohamed-Elamir F HegazyPeter A SidhomPublished in: Pharmaceuticals (Basel, Switzerland) (2022)
The main protease (M pro ) is a potential druggable target in SARS-CoV-2 replication. Herein, an in silico study was conducted to mine for M pro inhibitors from toxin sources. A toxin and toxin-target database (T3DB) was virtually screened for inhibitor activity towards the M pro 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 M pro 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 M pro inhibitor and warrants further in vitro/in vivo validation.
Keyphrases
- molecular dynamics
- molecular docking
- sars cov
- density functional theory
- molecular dynamics simulations
- escherichia coli
- anti inflammatory
- respiratory syndrome coronavirus
- dna binding
- binding protein
- adverse drug
- gene expression
- drinking water
- coronavirus disease
- single molecule
- early onset
- single cell
- preterm birth
- artificial intelligence
- big data
- dengue virus
- zika virus
- low birth weight
- data analysis