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Open AccessArticle

Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell–Cell Adhesion

1
Center for Nano Science and Technology @PoliMi, Istituto Italiano di Tecnologia, Via Pascoli 70/3, 20133 Milano, Italy
2
Computational Sciences, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
3
Department of Pharmacy and Biotechnology, University of Bologna, via Belmeloro 6, 40121 Bologna, Italy
4
Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 13273 Marseille CEDEX 09, France
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(14), 3404; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20143404
Received: 8 June 2019 / Revised: 6 July 2019 / Accepted: 8 July 2019 / Published: 11 July 2019
(This article belongs to the Special Issue Activations of Cadherin Signaling in Cancer)
Cadherins are a large family of transmembrane calcium-dependent cell adhesion proteins that orchestrate adherens junction formation and are crucially involved in tissue morphogenesis. Due to their important role in cancer development and metastasis, cadherins can be considered attractive targets for drug discovery. A recent crystal structure of the complex of a cadherin extracellular portion and a small molecule inhibitor allowed the identification of a druggable interface, thus providing a viable strategy for the design of cadherin dimerization modulators. Here, we report on a structure-based virtual screening approach that led to the identification of efficient and selective modulators of E-cadherin-mediated cell–cell adhesion. Of all the putative inhibitors that were identified and experimentally tested by cell adhesion assays using human pancreatic tumor BxPC-3 cells expressing both E-cadherin and P-cadherin, two compounds turned out to be effective in inhibiting stable cell–cell adhesion at micromolar concentrations. Moreover, at the same concentrations, one of them also showed anti-invasive properties in cell invasion assays. These results will allow further development of novel and selective cadherin-mediated cell–cell adhesion modulators for the treatment of a variety of cadherin-expressing solid tumors and for improving the efficiency of drug delivery across biological barriers. View Full-Text
Keywords: E-cadherin; P-cadherin; cell adhesion; cell invasion; inhibitor; structure-based virtual screening E-cadherin; P-cadherin; cell adhesion; cell invasion; inhibitor; structure-based virtual screening
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MDPI and ACS Style

Dalle Vedove, A.; Falchi, F.; Donini, S.; Dobric, A.; Germain, S.; Di Martino, G.P.; Prosdocimi, T.; Vettraino, C.; Torretta, A.; Cavalli, A.; Rigot, V.; André, F.; Parisini, E. Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell–Cell Adhesion. Int. J. Mol. Sci. 2019, 20, 3404. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20143404

AMA Style

Dalle Vedove A, Falchi F, Donini S, Dobric A, Germain S, Di Martino GP, Prosdocimi T, Vettraino C, Torretta A, Cavalli A, Rigot V, André F, Parisini E. Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell–Cell Adhesion. International Journal of Molecular Sciences. 2019; 20(14):3404. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20143404

Chicago/Turabian Style

Dalle Vedove, Andrea; Falchi, Federico; Donini, Stefano; Dobric, Aurelie; Germain, Sebastien; Di Martino, Giovanni P.; Prosdocimi, Tommaso; Vettraino, Chiara; Torretta, Archimede; Cavalli, Andrea; Rigot, Veronique; André, Frederic; Parisini, Emilio. 2019. "Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell–Cell Adhesion" Int. J. Mol. Sci. 20, no. 14: 3404. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20143404

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