A Common Anesthetic Binding Site among Atrial Fibrillation-Relevant Ion Channels: Application to Polypharmacological Rational Drug Identification
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Abstract
The physiology of cardiac tissues is fundamentally driven by ion channels, which regulate action potentials essential for the cardiac cycle. Alterations in ion channel behavior can lead to abnormal cardiac phenomena, such as atrial fibrillation (AF), the most common arrhythmic condition worldwide. In this context, potassium channels hKv1.5 and hTASK-1, along with the sodium channel hNav1.5, are promising drug targets for AF treatment due to their significant role in this pathology.
A modern drug research paradigm, polypharmacology, offers a novel strategy to address AF by leveraging the involvement of multiple targets. This approach focuses on the design and development of multi-target-directed ligands (MTDLs) that modulate several ion channels within the same potency range.
Local anesthetic (LA) drugs, including ropivacaine, bupivacaine, and lidocaine, are well-documented to bind and block these three ion channels. To investigate the dynamics of LA interactions with their binding sites (BSs), alanine scanning mutagenesis was performed to identify ropivacaine and bupivacaine BSs in hKv1.5. Additionally, molecular docking calculations were conducted for ropivacaine and bupivacaine in Kv1.5, lidocaine in Nav1.5 and bupivacaine in hTASK-1 using previously reported LA BSs.
To apply this structural information toward MTDL drug design, two approaches were employed. The first utilized the pharmacophore model of LAs to guide the chemical synthesis of compounds maintaining key features of LA pharmacophores, followed by ranking based on molecular docking and MM-GBSA energy calculations. The second approach applied the LA pharmacophore as a filter for the FDA database, creating a drug library. In silico models of hKv1.5, hNav1.5, and hTASK-1 were then developed to identify shared binding pockets, incorporating membrane-embedded systems of bupivacaine/ropivacaine-hKv1.5, lidocaine-rNav1.5, and bupivacaine-hTASK-1. Molecular dynamics simulations were conducted to characterize and compare these BSs based on their physicochemical and geometric features. Utilizing these data, a new computational workflow was established, proposing a common LA-binding pattern (receptophore) across these ion channels. A virtual screening process guided by the receptophore was subsequently performed using the generated drug library.
Hits identified through both approaches were tested in electrophysiological experiments, leading to the discovery of novel MTDLs that selectively block hKv1.5, hTASK-1, and hNav1.5.
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Issued: 2025-10-16
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Is based on: https://doi.org/10.1016/j.jbc.2025.108387Is based on: https://doi.org/10.3390/pharmaceutics14071356Is based on: https://doi.org/10.1111/bph.15480
Faculty
FB20:Medizin
Language
en
Keywords
polypharmacologyAtrial fibrillationDrug repurposingMulti-target directed ligandNav1.5Kv1.5TASK-1
DFG-subjects
205-09 Pharmakologie201-02 Biophysik201-04 Strukturbiologie323-01 Physikalische Chemie von Molekülen, Flüssigkeiten und Grenzflächen, Biophysikalische Chemie
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Márquez Montesinos, José Carlos Estanislao: A Common Anesthetic Binding Site among Atrial Fibrillation-Relevant Ion Channels: Application to Polypharmacological Rational Drug Identification. : 2025-10-16.
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Except where otherwised noted, this item's license is described as Attribution-NonCommercial 4.0 International