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

• Type: Article in International Scientific Journal
• Date: 2023

Authors

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

Journal

Title: ACS Omega

Vol. 8

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 0 Citations

Scopus

Other information

Authenticus ID: 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 7