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Exploring the Mechanism of Activation of CFTR by Curcuminoids: An Ensemble Docking Study
Version 1
: Received: 7 November 2023 / Approved: 8 November 2023 / Online: 8 November 2023 (04:12:50 CET)
A peer-reviewed article of this Preprint also exists.
Bellacchio, E. Exploring the Mechanism of Activation of CFTR by Curcuminoids: An Ensemble Docking Study. Int. J. Mol. Sci. 2024, 25, 552. Bellacchio, E. Exploring the Mechanism of Activation of CFTR by Curcuminoids: An Ensemble Docking Study. Int. J. Mol. Sci. 2024, 25, 552.
Abstract
Curcumin, a major constituent of turmeric, has beneficial effects against several diseases. In cystic fibrosis (CF), this compound potentiates the activity of a number of cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Despite holding promise in the treatment of CF, the curcumin binding site in CFTR and the molecular mechanism of activation of this channel are still unknown. The results of the study, based on docking and molecular dynamics (MD) simulations, allow to propose that curcumin binds the closed ATP-free CFTR near the NBD1/ ICl1/ICl4 interface. The bound ligand, once approached by NBD2 during transient channel opening, lays at a multiple interdomain cross point. Thereafter, curcumin can bridge NBD1 and NBD2, and also ICL1/ICL4 and ICL2/ICL3 finally tightening the same interdomain interactions that normally uphold the active conformation in the wild type ATP-bound CFTR. The proposed binding site is compatible with biochemical observations made in previous CFTR-curcumin interaction studies. These findings provide the framework for the design of novel drugs that activate CFTR mutants characterized by defects in ATP binding and/or NBD dimerization, or even lacking NBD2.
Keywords
CFTR; cystic fibrosis; cystic fibrosis transmembrane conductance regulator; docking; molecular dynamics; curcumin; CFTR modulators
Subject
Medicine and Pharmacology, Medicine and Pharmacology
Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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