Related Experiment Video
Updated: Jun 13, 2026
05:08
Application of I TASSER, trRosetta, UCSF Chimera, HADDOCK server, and HEX loria for De Novo and In Silico Design of Proteins
Published on: July 8, 2025
ARumenamides as Multitarget Ion Channel Modulators: Insights from Fenestration-Focused Docking, ADMET Profiling, and
Mena Abdelsayed1, Yassir Boulaamane2
1Lankenau Institute for Medical Research, Philadelphia, PA 19096, USA.
International Journal of Molecular Sciences
|June 12, 2026
Summary
Novel ARumenamides show potential as multitarget ion channel modulators for treating cardiac and neuromuscular disorders. Computational studies reveal specific binding sites and favorable safety profiles for developing new polypharmacological therapies.
Area of Science:
- Pharmacology
- Computational Chemistry
- Structural Biology
Background:
- Voltage-gated ion channels are crucial for muscle and nerve function.
- Dysfunction leads to channelopathies like arrhythmias and neuromuscular disorders.
- Polypharmacology, targeting multiple ion channel subtypes, offers therapeutic potential.
Purpose of the Study:
- To investigate the multitarget binding mechanisms of ARumenamide derivatives.
- To evaluate their potential as polypharmacological therapeutics for ion channelopathies.
- To establish a structure-dynamics framework for rational ARumenamide design.
Main Methods:
- Structure-based computational workflow including molecular docking.
- In silico ADMET profiling for safety and absorption assessment.
- Long-timescale molecular dynamics simulations (250 ns) on 15 ion channel structures.
Main Results:
- ARumenamides demonstrated broad multitarget binding across sodium, calcium, and potassium channels.
- Most derivatives showed favorable ADMET profiles, with some exceptions.
- Molecular dynamics revealed site-specific binding and dynamic retention for prioritized compounds (AR-310, AR-769, AR-946).
Conclusions:
- ARumenamides can act as multitarget ion channel modulators.
- Fenestration-focused binding offers sustained ligand engagement without pore occlusion.
- This study provides a framework for designing novel polypharmacological therapeutics for channelopathies.
Related Concept Videos
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
01:19Ligand-gated Ion Channels
Ligand-gated ion channels are transmembrane proteins with a channel for ions to pass through and a binding site for a ligand. The channel opens only when a ligand attaches to the binding site.
Three Subfamilies of Ligand-gated Ion Channels
Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that include the...
Three Subfamilies of Ligand-gated Ion Channels
Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that include the...
01:18Patch Clamp
Many fundamental cell functions such as muscle contraction and nerve transmission rely on the electrical signals produced by the movement of positively and negatively charged ions across the cell membrane. One competent method to record current flowing across the whole cell or single ion channel is the patch-clamp technique.
In this method, a glass micropipette containing electrolyte solution is tightly sealed against a small portion of the cell membrane. As a result, a patch of the cell...
In this method, a glass micropipette containing electrolyte solution is tightly sealed against a small portion of the cell membrane. As a result, a patch of the cell...
01:26Targets for Drug Action: Overview
Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
01:16Adrenergic Agonists: Chemistry and Structure-Activity Relationship
Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...