{
  "abstract": "Introduction The vascular endothelial growth factor (VEGF) receptor 2, a membrane tyrosine kinase receptor, together with its native ligand VEGF-A, triggers endothelial cell proliferation, migration, survival, and the formation of new blood vessels, all crucial functions for angiogenesis (Abhinand, C. S. et al., 2016). In systemic sclerosis, all VEGF receptors are upregulated in the skin, with pronounced VEGFR-2 expression on endothelial cells, suggesting dysregulated VEGF signaling (Distler, O. et al., 2004). In contrast, late-outgrowth endothelial progenitor cells fail to upregulate VEGFR-1 under hypoxic conditions, thereby amplifying VEGF/VEGFR-2 signaling and promoting abnormal vascular morphology and function (Avouac, J. et al., 2008). VEGFR inhibitors are categorized based on receptor conformation and their mechanism of ATP competition. These inhibitors work by inducing a conformational change in the receptor’s DFG motif, creating an additional hydrophobic pocket. The ligand/inhibitor binds to this pocket and the ATP-binding site to achieve inhibition (Sobhy, M. K. et al., 2019). With the aim of identifying additional new ligands or acquiring novel information to craft potent drugs, the focus of this study was to identify selective modulators or inhibitors of this macromolecular target.Material and Methods Pharmacophore search modalities were used to conduct ligand-based virtual screenings (LBVS) of large, pre-built libraries from popular compound databases such as PubChem and MolPort. Using the Pharmit server, we achieved pharmacophore-based screening on libraries containing about 450 million compounds, resulting in a set of ligands/inhibitors, which were tested using molecular modeling tools such as molecular docking, molecular dynamics (MD), and three-dimensional quantitative structure–activity relationship analysis.Results The LBVS identified a set of 53 potential ligands, each characterized by a minimum pharmacophore RMSD value and a high affinity for VEGFR2, as validated by molecular docking. MD simulations demonstrated that the complexes achieved stability (RMSD value below 0.6 nm) within 5 ns, with the compounds binding exclusively to the extended hydrophobic pocket of VEGFR2. The most stable complex closely matched the proposed pharmacophore model -an integration of previous models- exhibiting nanomolar affinity. This affinity is consistent with values typical of effective drug inhibition and reliable QSAR analysis. These findings indicate that the steric model offers greater consistency and robustness compared to the electrostatic model, as confirmed by MD results.Conclusions While experimental evidence remains mandatory to decipher the mechanisms underlying VEGFR2 inhibitors, the structural insights gleaned from this research hold promise for advancing the development of increasingly potent and precisely targeted therapies for VEGFR-associated conditions, such as cancer and fibrosis-related diseases.",
  "authors": [
    {
      "affiliations": [
        "Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy"
      ],
      "name": "Matteo Mozzicafreddo"
    },
    {
      "affiliations": [
        "Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy",
        "Department of Internal Medicine, Marche University Hospital, Ancona, Italy"
      ],
      "name": "Devis Benfaremo"
    },
    {
      "affiliations": [
        "Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy"
      ],
      "name": "Silvia Agarbati"
    },
    {
      "affiliations": [
        "Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy"
      ],
      "name": "Carolina Clementi"
    },
    {
      "affiliations": [
        "Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy"
      ],
      "name": "Chiara Paolini"
    },
    {
      "affiliations": [
        "Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy",
        "Department of Internal Medicine, Marche University Hospital, Ancona, Italy"
      ],
      "name": "Silvia Svegliati Baroni"
    },
    {
      "affiliations": [
        "Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy",
        "Department of Internal Medicine, Marche University Hospital, Ancona, Italy"
      ],
      "name": "Gianluca Moroncini"
    }
  ],
  "title": "P.231 Exploring potential VEGF receptor 2 inhibitors: a molecular modeling and pharmacophore-based screening approach",
  "uid": "e6d558d9-594d-54d9-baae-58b1e0acf531"
}