ARumenamides as Multitarget Ion Channel Modulators: Insights from Fenestration-Focused Docking, ADMET Profiling, and Molecular Dynamics.

Voltage-gated ion channels are central regulators of cardiac, neuronal, and skeletal muscle excitability, and their dysfunction underlies a wide spectrum of channelopathies, including arrhythmias and neuromuscular disorders. While conventional ion channel therapeutics typically target a single pore-binding site, emerging evidence supports the therapeutic potential of polypharmacological compounds capable of modulating multiple channel subtypes. ARumenamides represent a novel class of sulfonamide-based ligands originally identified as fenestration-targeting sodium channel modulators; however, their cross-family binding mechanisms and multitarget potential remain incompletely defined. Here, we employed an integrated structure-based computational workflow combining molecular docking, in silico ADMET profiling, and long-timescale (250 ns) molecular dynamics simulations to systematically evaluate 20 ARumenamide derivatives across 15 voltage-gated sodium, calcium, and potassium channel structures. Docking analyses revealed broad multitarget binding profiles, with several compounds exhibiting high predicted affinity across cardiac, neuronal, and skeletal muscle channel isoforms. ADMET predictions demonstrated favorable intestinal absorption and metabolic safety for most candidates, although solubility and mutagenicity liabilities were identified for select derivatives. Detailed molecular dynamics simulations of prioritized compounds (AR-310, AR-769, and AR-946) uncovered site-specific binding behaviors and conformational effects. AR-769 exhibited exceptional stability at both fenestration and central pore sites of Cav1.2, associated with persistent hydrogen-bond networks, reduced protein flexibility, and a well-defined free energy minimum. In contrast, AR-310 and AR-946 displayed selective stability within Nav1.4 fenestrations and the Kv4.3 central pore, respectively, highlighting how subtle chemical features bias binding site preference and dynamic retention. Collectively, these findings establish a structure-dynamics framework for rational design of ARumenamide-based multitarget ion channel modulators. Our results demonstrate that fenestration-focused binding can support sustained ligand engagement without obligatory pore occlusion, offering a mechanistically distinct strategy for developing next-generation polypharmacological therapeutics for cardiac and neuromuscular disorders.