Molecular interactions between a diphenyl scaffold and PED/PEA15: Implications for type II diabetes therapeutics targeting PED/PEA15 - Phospholipase D1 interaction.

Autor:	Mercurio I; Institute of Crystallography, CNR, Via Amendola 122/o, 70126 Bari, Italy.; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', Via Vivaldi 43, 81100 Caserta, Italy., D'Abrosca G; Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy.; Institute of Crystallography, CNR, Via Vivaldi 43, 81100, Caserta, Italy., Della Valle M; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', Via Vivaldi 43, 81100 Caserta, Italy., Malgieri G; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', Via Vivaldi 43, 81100 Caserta, Italy., Fattorusso R; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', Via Vivaldi 43, 81100 Caserta, Italy., Isernia C; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', Via Vivaldi 43, 81100 Caserta, Italy., Russo L; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', Via Vivaldi 43, 81100 Caserta, Italy., Di Gaetano S; Institute of Biostructures and Bioimaging, CNR, Via P. Castellino 111, 80131 Naples, Italy., Pedone EM; Institute of Biostructures and Bioimaging, CNR, Via P. Castellino 111, 80131 Naples, Italy., Pirone L; Institute of Biostructures and Bioimaging, CNR, Via P. Castellino 111, 80131 Naples, Italy., Del Gatto A; Institute of Biostructures and Bioimaging, CNR, Via P. Castellino 111, 80131 Naples, Italy., Zaccaro L; Institute of Biostructures and Bioimaging, CNR, Via P. Castellino 111, 80131 Naples, Italy., Alberga D; Institute of Crystallography, CNR, Via Amendola 122/o, 70126 Bari, Italy., Saviano M; Institute of Crystallography, CNR, Via Vivaldi 43, 81100, Caserta, Italy., Mangiatordi GF; Institute of Crystallography, CNR, Via Amendola 122/o, 70126 Bari, Italy.
Jazyk:	angličtina
Zdroj:	Computational and structural biotechnology journal [Comput Struct Biotechnol J] 2024 May 04; Vol. 23, pp. 2001-2010. Date of Electronic Publication: 2024 May 04 (Print Publication: 2024).
DOI:	10.1016/j.csbj.2024.04.063
Abstrakt:	In a recent study, we have identified BPH03 as a promising scaffold for the development of compounds aimed at modulating the interaction between PED/PEA15 (Phosphoprotein Enriched in Diabetes/Phosphoprotein Enriched in Astrocytes 15) and PLD1 (phospholipase D1), with potential applications in type II diabetes therapy. PED/PEA15 is known to be overexpressed in certain forms of diabetes, where it binds to PLD1, thereby reducing insulin-stimulated glucose transport. The inhibition of this interaction reestablishes basal glucose transport, indicating PED as a potential target of ligands capable to recover glucose tolerance and insulin sensitivity. In this study, we employ computational methods to provide a detailed description of BPH03 interaction with PED, evidencing the presence of a hidden druggable pocket within its PLD1 binding surface. We also elucidate the conformational changes that occur during PED interaction with BPH03. Moreover, we report new NMR data supporting the in-silico findings and indicating that BPH03 disrupts the PED/PLD1 interface displacing PLD1 from its interaction with PED. Our study represents a significant advancement toward the development of potential therapeutics for the treatment of type II diabetes. Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (© 2024 The Authors.)
Databáze:	MEDLINE
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