Format

Send to

Choose Destination
PeerJ. 2018 May 2;6:e4680. doi: 10.7717/peerj.4680. eCollection 2018.

From in silico to in vitro: a trip to reveal flavonoid binding on the Rattus norvegicus Kir6.1 ATP-sensitive inward rectifier potassium channel.

Author information

1
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
2
Toscana Life Sciences Foundation, Siena, Italy.
3
Department of Life Sciences, University of Siena, Siena, Italy.

Abstract

Background:

ATP-sensitive inward rectifier potassium channels (Kir), are a potassium channel family involved in many physiological processes. KATP dysfunctions are observed in several diseases such as hypoglycaemia, hyperinsulinemia, Prinzmetal angina-like symptoms, cardiovascular diseases.

Methods:

A broader view of the KATP mechanism is needed in order to operate on their regulation, and in this work we clarify the structure of the Rattus norvegicus ATP-sensitive inward rectifier potassium channel 8 (Kir6.1), which has been obtained through a homology modelling procedure. Due to the medical use of flavonoids, a considerable increase in studies on their influence on human health has recently been observed, therefore our aim is to study, through computational methods, the three-dimensional (3D) conformation together with mechanism of action of Kir6.1 with three flavonoids.

Results:

Computational analysis by performing molecular dynamics (MD) and docking simulation on rat 3D modelled structure have been completed, in its closed and open conformation state and in complex with Quercetin, 5-Hydroxyflavone and Rutin flavonoids. Our study showed that only Quercetin and 5-Hydroxyflavone were responsible for a significant down-regulation of the Kir6.1 activity, stabilising it in a closed conformation. This hypothesis was supported by in vitro experiments demonstrating that Quercetin and 5-Hydroxyflavone were capable to inhibit KATP currents of rat tail main artery myocytes recorded by the patch-clamp technique.

Conclusion:

Combined methodological approaches, such as molecular modelling, docking and MD simulations of Kir6.1 channel, used to elucidate flavonoids intrinsic mechanism of action, are introduced, revealing a new potential druggable protein site.

KEYWORDS:

ATP-sensitive inward rectifier potassium channel; Binding site; Flavonoid; Homology modeling; Kir6.1; Molecular docking; Molecular dynamics; Patch clamp; Potassium channel

Conflict of interest statement

Vittoria Cicaloni is a PhD student with a scholarship financed by Toscana Life Sciences Foundation, Siena, Italy.

Supplemental Content

Full text links

Icon for PeerJ, Inc. Icon for PubMed Central
Loading ...
Support Center