A combined fragment-based virtual screening and STD-NMR approach for the identification of E-cadherin ligands
Articolo
Data di Pubblicazione:
2022
Citazione:
A combined fragment-based virtual screening and STD-NMR approach for the identification of E-cadherin ligands / F. Vasile, F. Lavore, S. Gazzola, C. Vettraino, E. Parisini, U. Piarulli, L. Belvisi, M. Civera. - In: FRONTIERS IN CHEMISTRY. - ISSN 2296-2646. - 10:(2022), pp. 946087.1-946087.13. [10.3389/fchem.2022.946087]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
STD-NMR; cadherins; fragment virtual screening; molecular dynamics; protein–protein interaction (PPI)
Elenco autori:
F. Vasile, F. Lavore, S. Gazzola, C. Vettraino, E. Parisini, U. Piarulli, L. Belvisi, M. Civera
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