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

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.

In Silico Mining of Natural Products Atlas (NPAtlas) Database for Identifying Effective Bcl-2 Inhibitors: Molecular Docking, Molecular Dynamics, and Pharmacokinetics Characteristics

“…All molecular dynamic (MD) simulations were conducted using AMBER16 software [ 41 ]. The specifics of the MD simulations are characterized elsewhere [ 42 , 43 , 44 , 45 ]. Briefly, the AMBER force field of 14SB was used to characterize the Bcl-2 protein [ 46 ].…”

Eryngium creticum L.: Chemical Characterization, SARS-CoV-2 Inhibitory Activity, and In Silico Study

“…The outstanding performance of the AutoDock4.2.6 software in disclosing the inhibitor-3CL pro binding mode was previously reported, giving a predicted binding mode for XF7 with a root-mean-square deviation (rmsd) of 0.20 Å, compared to the resolved experimental binding mode. 23 Therefore, a molecular docking technique was used to predict the binding modes and affinities of the isolated compounds for 3CL pro , and these were compared to those of lopinavir as a reference. The predicted docking scores and binding features for the isolated compounds are listed in Table 2 .…”

“…In MD simulations, the General AMBER force field (GAFF2) and AMBER force field 14SB were employed to describe the studied compounds and 3CL pro , respectively. The specifics of the utilized MD simulations are elucidated in refs and – . In concise, the atomic partial charges of the examined compounds were calculated using the restrained electrostatic potential approach with the help of Gaussian 09 software .…”

Exploring Probenecid Derived 1,3,4-Oxadiazole-Phthalimide Hybrid as α-Amylase Inhibitor: Synthesis, Structural Investigation, and Molecular Modeling

“…The employed docking calculations are detailedly described elsewhere [ 65 , 66 , 67 ]. Briefly, the α-amylase crystal structure (PDB access code: 1ose [ 56 ]) complexed with acarbose was retrieved and employed as a template for docking predictions.…”