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, Emı́lia Sousa, Jean‐Pierre Gillet, M. Natália D. S. Cordeiro, Daniel J. V. A. dos Santos
Abstract
High Resolution Image Download MS PowerPoint Slide 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 IC 50 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.