| Autor: |
Francesca Vasile, Francesca Lavore, Silvia Gazzola, Chiara Vettraino, Emilio Parisini, Umberto Piarulli, Laura Belvisi, Monica Civera |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Frontiers in Chemistry, Vol 10 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2296-2646 |
| DOI: |
10.3389/fchem.2022.946087 |
| Popis: |
Cadherins promote cell-cell adhesion by forming homophilic interactions via their N-terminal extracellular domains. Hence, they have broad-ranging physiological effects on tissue organization and homeostasis. When dysregulated, cadherins contribute to different aspects of cancer progression and metastasis; therefore, targeting the cadherin adhesive interface with small-molecule antagonists is expected to have potential therapeutic and diagnostic value. Here, we used molecular docking simulations to evaluate the propensity of three different libraries of commercially available drug-like fragments (nearly 18,000 compounds) to accommodate into the Trp2 binding pocket of E-cadherin, a crucial site for the orchestration of the protein’s dimerization mechanism. Top-ranked fragments featuring five different aromatic chemotypes were expanded by means of a similarity search on the PubChem database (Tanimoto index >90%). Of this set, seven fragments containing an aromatic scaffold linked to an aliphatic chain bearing at least one amine group were finally selected for further analysis. Ligand-based NMR data (Saturation Transfer Difference, STD) and molecular dynamics simulations suggest that these fragments can bind E-cadherin mostly through their aromatic moiety, while their aliphatic portions may also diversely engage with the mobile regions of the binding site. A tetrahydro-β-carboline scaffold functionalized with an ethylamine emerged as the most promising fragment. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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