The structures of the 6 simulated phenolic compounds were built using 2 different strategies. Hydroxytyrosol, tyrosol, oleacein, and oleocanthal were downloaded from PubChem, while Ole and La were first downloaded from PubChem in their glucoside form and then manually modified to their aglycone form using the Molecular Editor functions of the VEGA suite of programs. The obtained structures were then minimized by using AMMP as implemented in the VEGA environment [27].

Among the resolved DPP-IV structures, this study involved the complex between the enzyme and the inhibitor 75 M, PDB ID: 5T4F, chosen due to its very high resolution (1.90 Å). After deleting water molecules ions and crystallographic additives, the selected dimer was completed by adding the hydrogen atoms to amino acid residues and ionizing the protein considering physiologic pH at 7.4. The H++ server was chosen to predict the protonation state of ionizable protein groups. The protein was then refined by 2 minimization procedures using NAMD [28]. The first procedure was carried out with all the protein atoms fixed except for hydrogens; the second was performed with the backbone atoms under constraints to preserve the resolved folding. The prepared protein structure underwent the following docking simulations.

Docking simulations were carried out using PLANTS (Protein-Ligand ANT System) [29], which generates reliable ligand poses using the ant colonization algorithm (ACO). In detail, the search was focused on a 10 Å radius sphere around the bound ligand 75 M, thus including the entire binding cavity. For all the simulated ligands, PLANTS was used with default settings and without geometric constraints, speed 1 was used, and 100 poses were generated and scored by using the ChemPLP function. The obtained poses were evaluated considering both the docking scores and the involved residues.

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