Extraction and characterization of metabolites from Olea europaea pulp and their molecular docking against SARS-CoV-2 main-protease (Mpro).

The present study is the first to extract the bioactive metabolites from Olea europaea fruit using the Soxhlet-maceration extraction method. The preliminary phytochemical; Fourier transform-infrared spectroscopy (FT-IR); gas chromatography-mass spectrometry (GC-MS) analyses, and their potential against SARS-CoV-2 Mpro through molecular docking were studied. The preliminary qualitative phytochemical analyses showed coumarin glycosides, tannins, terpenoids, cholesterol, carbohydrates, and proteins. FT-IR spectroscopy revealed C-H, C = O, O-H, C-N, C-O-C, C-O, CO-O-CO, C = C, and C-Br functional groups in the extract. GC-MS analysis was done and the compounds detected were docked against SARS-CoV-2 Mpro using AutoDock Vina.The squalene (ΔG = -6.2 kcal/mol) posed the best inhibition potential and was comparable with the control drug remdesivir. The compounds possessed excellent pharmacokinetic and toxicity properties and are safe and reliable. Thus, the present research unveiled the valuable metabolites from O. europaea and their antiviral potential against the SARS-CoV-2.

Modelling and targeting mitochondrial protein tyrosine phosphatase 1: a computational approach.

The present research scintillates on the homology modelling of rat mitochondrial protein tyrosine phosphatase 1 (PTPMT1) and targeting its activity using flavonoids through a computational docking approach. PTPMT1 is a dual-specificity phosphatase responsible for protein phosphorylation and plays a vital role in the metabolism of cardiolipin biosynthesis, insulin regulation, etc. The inhibition of PTPMT1 has also shown enhanced insulin levels. The three-dimensional structure of the protein is not yet known. The homology modelling was performed using SWISS-MODEL and Geno3D webservers to compare the efficiencies. The PROCHECK for protein modelled using SWISS-MODEL showed 91.6% of amino acids in the most favoured region, 0.7% residues in the disallowed region that was found to be significant compared to the model built using Geno3D. 210 common flavonoids were docked in the modelled protein using the AutoDock 4.2.6 along with a control drug alexidine dihydrochloride. Our results show promising candidates that bind protein tyrosine phosphatase 1, including, prunin (- 8.66 kcal/mol); oroxindin (- 8.56 kcal/mol); luteolin 7-rutinoside (- 8.47 kcal/mol); 3(2H)-isoflavenes (- 8.36 kcal/mol); nicotiflorin (- 8.29 kcal/mol), ranked top in the docking experiments. We predicted the pharmacokinetic and Lipinski properties of the top ten compounds with the lowest binding energies. To further validate the stability of the modelled protein and docked complexes molecular dynamics simulations were performed using Desmond, Schrodinger for 150 ns in conjunction with MM-GBSA. Thus, flavonoids could act as potential inhibitors of PTPMT1, and further, in-vitro and in-vivo studies are essential to complete the drug development process.

Molecular docking, validation, dynamics simulations, and pharmacokinetic prediction of natural compounds against the SARS-CoV-2 main-protease.

The study aims to evaluate the potency of two hundred natural antiviral phytocompounds against the active site of the Severe Acquired Respiratory Syndrome - Coronavirus - 2 (SARS-CoV-2) Main-Protease (Mpro) using AutoDock 4.2.6. The three- dimensional crystal structure of the Mpro (PDB Id: 6LU7) was retrieved from the Protein Data Bank (PDB), the active site was predicted using MetaPocket 2.0. Food and Drug Administration (FDA) approved viral protease inhibitors were used as standards for comparison of results. The compounds theaflavin-3-3'-digallate, rutin, hypericin, robustaflavone, and (-)-solenolide A with respective binding energy of -12.41 (Ki = 794.96 pM); -11.33 (Ki = 4.98 nM); -11.17 (Ki = 6.54 nM); -10.92 (Ki = 9.85 nM); and -10.82 kcal/mol (Ki = 11.88 nM) were ranked top as Coronavirus Disease - 2019 (COVID-19) Mpro inhibitors. The interacting amino acid residues were visualized using Discovery Studio 3.5 to elucidate the 2-dimensional and 3-dimensional interactions. The study was validated by i) re-docking the N3-peptide inhibitor-Mpro and superimposing them onto co-crystallized complex and ii) docking decoy ligands to Mpro. The ligands that showed low binding energy were further predicted for and pharmacokinetic properties and Lipinski's rule of 5 and the results are tabulated and discussed. Molecular dynamics simulations were performed for 50 ns for those compounds using the Desmond package, Schrödinger to assess the conformational stability and fluctuations of protein-ligand complexes during the simulation. Thus, the natural compounds could act as a lead for the COVID-19 regimen after in-vitro and in- vivo clinical trials.Communicated by Ramaswamy H. Sarma.