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.

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]

A combined fragment-based virtual screening and STD-NMR approach for the identification of E-cadherin ligands

F. Vasile
Primo
;
L. Belvisi
Penultimo
;
M. Civera
Ultimo
2022

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.
STD-NMR; cadherins; fragment virtual screening; molecular dynamics; protein–protein interaction (PPI)
Settore CHIM/06 - Chimica Organica
PRIN202022CGENN_01 - Synthesis and biomedical applications of tumor targeting peptidomimetics and conjugates - GENNARI, CESARE MARIO ARTURO - PRIN2020 - PRIN bando 2020 - 2022
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/939651
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