1. A combined fragment-based virtual screening and STD-NMR approach for the identification of E-cadherin ligands
- Author
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Vasile, Francesca, Lavore, Francesca, Gazzola, Silvia, Vettraino, Chiara, Parisini, Emilio, Piarulli, Umberto, Belvisi, Laura, Civera, Monica, Vasile, Francesca, Lavore, Francesca, Gazzola, Silvia, Vettraino, Chiara, Parisini, Emilio, Piarulli, Umberto, Belvisi, Laura, and Civera, Monica
- Subjects
STD-NMR ,cadherins ,fragment virtual screening ,molecular dynamics ,protein–protein interaction (PPI) ,fragment virtual screening, molecular dynamics, STD-NMR, cadherins, protein–protein interaction (PPI) ,Settore CHIM/06 - Chimica Organica - Abstract
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.
- Published
- 2022