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Molecular interactions between a diphenyl scaffold and PED/PEA15: Implications for type II diabetes therapeutics targeting PED/PEA15 - Phospholipase D1 interaction.
Mercurio, Ivan; D'Abrosca, Gianluca; Della Valle, Maria; Malgieri, Gaetano; Fattorusso, Roberto; Isernia, Carla; Russo, Luigi; Di Gaetano, Sonia; Pedone, Emilia Maria; Pirone, Luciano; Del Gatto, Annarita; Zaccaro, Laura; Alberga, Domenico; Saviano, Michele; Mangiatordi, Giuseppe Felice.
Afiliación
  • Mercurio I; Institute of Crystallography, CNR, Via Amendola 122/o, 70126 Bari, Italy.
  • D'Abrosca G; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Via Vivaldi 43, 81100 Caserta, Italy.
  • Della Valle M; Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy.
  • Malgieri G; Institute of Crystallography, CNR, 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; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Via Vivaldi 43, 81100 Caserta, Italy.
  • Pedone EM; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Via Vivaldi 43, 81100 Caserta, 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 Biostructures and Bioimaging, CNR, Via P. Castellino 111, 80131 Naples, Italy.
  • Saviano M; Institute of Biostructures and Bioimaging, CNR, Via P. Castellino 111, 80131 Naples, Italy.
  • Mangiatordi GF; Institute of Crystallography, CNR, Via Amendola 122/o, 70126 Bari, Italy.
Comput Struct Biotechnol J ; 23: 2001-2010, 2024 Dec.
Article en En | MEDLINE | ID: mdl-38770160
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Comput Struct Biotechnol J Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Comput Struct Biotechnol J Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Países Bajos