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

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

doi:10.3390/ph15020153

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

Pharmaceuticals (Basel). 2022 Jan 27;15(2):153. doi: 10.3390/ph15020153.

Affiliations

¹ Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia 61519, Egypt.
² Department of Chemistry, Faculty of Science, Kuwait University, Kuwait City 13060, Kuwait.
³ Cardiovascular and Metabolic Sciences Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
⁴ Molecular Genetics and Genome Mapping Laboratory, Genome Mapping Department, Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center (ARC), Giza 12619, Egypt.
⁵ Department of Biology, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia.
⁶ Department of Chemistry, The University of Azad Jammu and Kashmir, Muzaffarabad 13100, Pakistan.
⁷ Molecular Modelling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa.
⁸ Science and Technology Unit (STU), Umm Al-Qura University, Makkah 21955, Saudi Arabia.
⁹ Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, TX 79409, USA.
¹⁰ Chemistry of Medicinal Plants Department, National Research Centre, 33 El-Bohouth St., Dokki, Giza 12622, Egypt.
¹¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.

Abstract

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.

Keywords: SARS-CoV-2 Mpro; in silico screening; molecular docking calculations; molecular dynamics (MD) simulations; reactome; toxins.

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

Authors

Affiliations

Abstract

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