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

Cátia A. Bonito, Ricardo J. Ferreira, Maria José U. Ferreira, Fernando Durães, Emília Sousa, Jean Pierre Gillet, M. Natália D.S. Cordeiro, Daniel J.V.A. dos Santos

Resultado de pesquisarevisão de pares

4 Citações (Scopus)

Resumo

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 μM is reported for a flavanone derivative in the ATPase assays, providing evidence for an allosteric efflux 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 originalInglês
Páginas (de-até)11281-11287
Número de páginas7
RevistaACS Omega
Volume8
Número de emissão12
DOIs
Estado da publicaçãoPublicadas - 28 mar. 2023

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© 2023 The Authors. Published by American Chemical Society.

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