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Article

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

by
Yuliet Mazola
1,†,
José C. E. Márquez Montesinos
1,†,
David Ramírez
2,
Leandro Zúñiga
3,
Niels Decher
4,
Ursula Ravens
5,
Vladimir Yarov-Yarovoy
6 and
Wendy González
1,7,*
1
Center for Bioinformatics, Simulation and Modeling (CBSM), Universidad de Talca, Talca 3460000, Chile
2
Departamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción 4030000, Chile
3
Escuela de Medicina, Centro de Investigaciones Médicas, Universidad de Talca, Talca 3460000, Chile
4
Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, 35043 Marburg, Germany
5
Institut für Experimentelle Kardiovaskuläre Medizin, Universitäts-Herzzentrum Freiburg Bad Krotzingen, 79110 Freiburg im Breisgau, Germany
6
Department of Physiology and Membrane Biology, University of California, Davis, CA 95616, USA
7
Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Talca 3530000, Chile
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Pharmaceutics 2022, 14(7), 1356; https://doi.org/10.3390/pharmaceutics14071356
Submission received: 14 May 2022 / Revised: 20 June 2022 / Accepted: 20 June 2022 / Published: 27 June 2022
(This article belongs to the Special Issue Multi-Target Drug Design for Complex Diseases)
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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 a 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 alterations in 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 present a computational workflow for a flecainide BS comparison in a flecainide-Kv1.5 docking model and a solved structure of the 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 central cavity and consists of a hydrophobic patch and a polar region, involving residues from the 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 atrial fibrillation; multi-target; drug promiscuity; druggable binding site; flecainide; Nav1.5; Kv1.5; binding site comparison; polypharmacology

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MDPI and ACS Style

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. https://doi.org/10.3390/pharmaceutics14071356

AMA Style

Mazola Y, Márquez Montesinos JCE, 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(7):1356. https://doi.org/10.3390/pharmaceutics14071356

Chicago/Turabian Style

Mazola, Yuliet, José C. E. Márquez Montesinos, David Ramírez, Leandro Zúñiga, Niels Decher, Ursula Ravens, Vladimir Yarov-Yarovoy, and Wendy González. 2022. "Common Structural Pattern for Flecainide Binding in Atrial-Selective Kv1.5 and Nav1.5 Channels: A Computational Approach" Pharmaceutics 14, no. 7: 1356. https://doi.org/10.3390/pharmaceutics14071356

APA Style

Mazola, Y., Márquez Montesinos, J. C. E., Ramírez, D., Zúñiga, L., Decher, N., Ravens, U., Yarov-Yarovoy, V., & González, W. (2022). Common Structural Pattern for Flecainide Binding in Atrial-Selective Kv1.5 and Nav1.5 Channels: A Computational Approach. Pharmaceutics, 14(7), 1356. https://doi.org/10.3390/pharmaceutics14071356

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