Identification of Binding Sites in the Nucleotide-Binding Domain of P-Glycoprotein for a Potent and Nontoxic Modulator, the Amine-Containing Monomeric Flavonoid FM04

Zhen Liu, Iris L.K. Wong, Jingcheng Sang, Fufeng Liu, Clare S.W. Yan, Jason W.Y. Kan, Tak Hang Chan, Larry M.C. Chow

Research output: Journal article publicationJournal articleAcademic researchpeer-review

2 Citations (Scopus)

Abstract

We have previously discovered an amine-containing flavonoid monomer FM04 as a potent P-glycoprotein (P-gp) inhibitor (EC50 = 83 nM). Here, a series of photoactive FM04 analogues were synthesized and used together with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify the FM04-binding sites on P-gp. Point mutations around the photo-crosslinked sites were made for verification. Together with the results from mutational studies, molecular docking, and molecular dynamics simulations, it was found that FM04 can interact with Q1193 and I1115 in the nucleotide-binding domain 2 (NBD2) of human P-gp. It was proposed that FM04 can inhibit P-gp in 2 novel mechanisms. FM04 can either bind to (1) Q1193, followed by interacting with the functionally critical residues H1195 and T1226 or (2) I1115 (a functionally critical residue itself), disrupting the R262-Q1081-Q1118 interaction pocket and uncoupling ICL2-NBD2 interaction and thereby inhibiting P-gp. Q1118 would subsequently be pushed to the ATP-binding site and stimulate ATPase.

Original languageEnglish
Pages (from-to)6160-6183
Number of pages24
JournalJournal of Medicinal Chemistry
Volume66
Issue number9
DOIs
Publication statusPublished - 11 May 2023

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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