Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Common Structural Pattern for Flecainide Binding in Atrial-Selective Kv1.5 and Nav1.5 Channels: A Computational Approach

Yuliet Mazola
,
José C.E. Márquez-Montesinos
ORCID logo ,
David Ramírez
,
Leandro Zúñiga
,
Niels Decher
ORCID logo ,
Ursula Ravens
ORCID logo ,
Vladimir Yarov-Yarovoy
,
Wendy González
* ORCID logo
Version 1 : Received: 29 May 2022 / Approved: 30 May 2022 / Online: 30 May 2022 (10:10:41 CEST)

A peer-reviewed article of this Preprint also exists.

Mazola, Y.; Márquez Montesinos, J.C.E.; Ramírez, D.; Zúñiga, L.; Decher, N.; Ravens, U.; Yarov-Yarovoy, V.; González, W. Common Structural Pattern for Flecainide Binding in Atrial-Selective Kv1.5 and Nav1.5 Channels: A Computational Approach. Pharmaceutics 2022, 14, 1356. Mazola, Y.; Márquez Montesinos, J.C.E.; Ramírez, D.; Zúñiga, L.; Decher, N.; Ravens, U.; Yarov-Yarovoy, V.; González, W. Common Structural Pattern for Flecainide Binding in Atrial-Selective Kv1.5 and Nav1.5 Channels: A Computational Approach. Pharmaceutics 2022, 14, 1356.

DOI: 10.3390/pharmaceutics14071356

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Its treatment includes antiarrhythmic drugs (AADs) to modulate the function of cardiac ion channels. However, AADs have been limited by proarrhythmic effects, non-cardiovascular toxicities as well as often modest antiarrhythmic efficacy. Theoretical models showed that combined blockade of Nav1.5 (and its current INa) and Kv1.5 (and its current, IKur) ion channels yield a synergistic anti-arrhythmic effect without effect on ventricles. We focused on Kv1.5 and Nav1.5 to search for structural similarities in their binding site (BS) for flecainide (a common blocker and widely prescribed AAD), as a first step for prospective rational multi-target directed ligand (MTDL) design strategies. We presented a computational workflow for flecainide BS comparison in a flecainide-Kv1.5 docking model and a solved structure of flecainide-Nav1.5 complex. The workflow includes docking, molecular dynamics, BS characterization and pattern matching. We identified a common structural pattern in flecainide BS for these channels. The latter belongs to the inner cavity and consist of a hydrophobic patch and a polar region, involving residues from S6 helix and P-loop. Since the rational MTDL design for AF is still incipient, our findings could advance multi-target atrial-selective strategies for AF treatment.

Keywords

atrial-fibrillation; multi-target; drug promiscuity; druggable binding site; flecainide; Nav1.5; Kv1.5; binding site comparison; polypharmacology

Subject

LIFE SCIENCES, Biophysics

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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