Probing the Allosteric Modulation of P-Glycoprotein: A Medicinal Chemistry Approach Toward the Identification of Noncompetitive P-Gp Inhibitors

• Tipo: Artigo em Revista Científica Internacional
• Data: 2023

Autores

Bonito, CA (Autor) Outra; Ferreira, RJ (Autor) Outra; Ferreira, MJU (Autor) Outra; Duraes, F (Autor) Outra; Emilia Sousa (Autor) FFUP; Gillet, JP (Autor) Outra; Natalia N D S Cordeiro (Autor) FCUP; dos Santos, DJVA (Autor) Outra

Revista

Título: ACS Omega

Vol. 8

Editora: American Chemical Society

Indexação

ISI Web of Knowledge - 0 Citações

Scopus

Outras Informações

ID Authenticus: P-00Y-3EN

DOI: 10.1021/acsomega.2c08273

Abstract (EN): A medicinal chemistry approach combining in silico and in vitro methodologies was performed aiming at identifying and characterizing putative allosteric drug-binding sites (aDBSs) at the interface of the transmembrane-and nucleotide-binding domains (TMD-NBD) of P-glycoprotein. Two aDBSs were identified, one in TMD1/NBD1 and another one in TMD2/NBD2, by means of in silico fragment-based molecular dynamics and characterized in terms of size, polarity, and lining residues. From a small library of thioxanthone and flavanone derivatives, experimentally described to bind at the TMD-NBD interfaces, several compounds were identified to be able to decrease the verapamil-stimulated ATPase activity. An IC50 of 81 +/- 6.6 mu M is reported for a flavanone derivative in the ATPase assays, providing evidence for an allosteric efux modulation in P-glycoprotein. Molecular docking and molecular dynamics gave additional insights on the binding mode on how flavanone derivatives may act as allosteric inhibitors.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 7