*3.2. Chemicals*

Analytical grade methanol was obtained from Macron Fine Chemicals (Avantor, Radnor, PA, USA); analytical grade dimethyl sulfoxide was obtained from FisherScientific (Fair Lawn, NJ, USA).Acetonitrile and formic acid for HPLC, gradient grade were purchased from Sigma-Aldrich (St. Louis, MO, USA). Arbidol hydrochloride (umifenovir) for HPLC (≥98%) and quercetin for HPLC (≥95%) reference standard were purchased from Sigma-Aldrich (St. Louis, MO, USA). Brevifolin carboxylic acid for HPLC (≥95%) reference standard was purchased from Cayman Chemical (Ann Arbor, MI, USA).

### *3.3. LC-MS Chemical Analysis*

The LC-MSanalysis of *A. viridiflora* methanol extract was performed and described in our earlier research, with an addition in this study relating to the software used for the identification of individual compounds [16]. Agilent Technologies HPLC1260 Infinity system connected to a single quadrupole mass detector (Singlequad MS detector 6130) was employed.Compound separation was carried out at 25 ◦C using a Zorbax SB Aq-C18 column (3.0 × 150 mm; 3.5 μm). Solvent A (0.1% HCOOH in water) and Solvent B (acetonitrile) were used for elution.With a flow rate of 0.3 mL/min, the gradient program listed below

was used: 0–30 min from 10% to 25% B; 30–35 min from 25% to 70% B; 35–40 minreturn to 10% B. Detection wavelengths were at 280 and 350 nm and in negative mode in a range of 50–2000 *m*/*z*. Electrospray ionization was carried out at a pressure of 40 psi, a temperature of 350 ◦C, and a nitrogen flow rate of 10 L/min. Signals from deprotonated molecules and fragmented ions were acquired in full-scan at fragmentation voltages of 100 V and 250 V. MestReNova v.12.0.0-20080 (Mestrelab Research, S.L., Santiago de Compostela, Spain) software'smolecule match tool was used for identification of compounds instead of tentative identification based on comparison with literature data, as it was performed in our previous study on this extract [16].

#### *3.4. Molecular Docking Simulations*

#### 3.4.1. Dataset

For the first target, the crystal structure of S-glycoprotein RBD in a complex with neutralizing body was retrieved from the Protein Data Bank (PDB; http://www.pdb.org, PDB ID:7BZ5) and prepared for docking by DockThor-VS web server as a new COVID-19 resources service (accesed and submitted on 11 May 2022). Besides the wild type S glycoprotein, docking studies were conducted on 9 mutation variants (V483A, N501Y-K417N-E484K, N501Y, N439K, L452R-T478K, K417N, G476S, F456L, E484K) of the same structure (PDB ID:7BZ5) [34]. For the second target, the crystal structure of the b1b2 domains from human neuropilin-1 (PDB ID:2QQI) was retrieved from PDB and prepared for the docking analysis using Yasara Structure (v. 20.4.24.W.64, YASARA Biosciences GmbH, Vienna, Austria) (http://www.yasara.org/; accessed on 11 May 2022). This procedure included deletion of solvents from the PDB files, adding hydrogens and charges to the structure, and the process of energy minimization. The 3D molecular structures of identified polyphenols and positive controls were downloaded from PubChem (https://pubchem. ncbi.nlm.nih.gov/; accessed on 11 May 2022) whereas compounds without 3D structures were downloaded as 2D structures and after that converted into 3D structures via online service (http://pccdb.org/tools/convert\_3D\_mol; accessed on 11 May 2022). All ligands' final geometries were energy minimized using the Yasara Structure energy minimization experiment option using AMBER03 force field at physiological pH (7.4), which ran local steepest descent minimization without electrostatics to eliminate bumps, followed by simulated annealing minimization energy with a certain energy improvement.

#### 3.4.2. Docking Parameters

Molecular docking simulations for the first target (PDB ID:7BZ5) were conducted inside a 20 Å size cubic grid box which was centered around Cα of Gln493 residue located at the binding zone of S glycoprotein and ACE-2 residues. For the second target (PDB ID:2QQI) grid box was generated around Asp320, Ser346, Thr316, Thr349 and Tyr353 residues within a distance of 5 Å. The docking procedure was conducted through Yasara Structure software based on the AutoDockVina algorithm and AMBER03 force field [35]. Output files of the most stable complexes were further analyzed with the visualization software (Discovery Studio Visualizer v.20.1.0.19295, Dassault Systèmes, Vélizy-Villacoublay, France).
