Ligand- and structure-based virtual screening for clathrodin-derived human voltage-gated sodium channel modulators

Area of Science:

• Pharmacology
• Medicinal Chemistry
• Neuroscience

Background:

• Voltage-gated sodium channels (VGSCs) are crucial drug targets due to the therapeutic potential of their modulators.
• Marine alkaloid clathrodin served as a structural basis for discovering novel VGSC modulators I and II.

Purpose of the Study:

• To discover novel VGSC modulators using ligand-based virtual screening approaches.
• To identify potent and subtype-selective modulators for therapeutic applications.

Main Methods:

• Ligand-based virtual screening of the ZINC database using compounds I and II as starting points.
• Similarity searching and molecular docking into homology models of human Na(v)1.4 and Na(v)1.7 channels.

Main Results:

• Similarity searching based on compound I identified five state-dependent Na(v)1.3 and Na(v)1.7 modulators, with compounds 2 and 16 showing high potency (IC₅₀ values of 7 and 9 μM for Na(v)1.7 block).
• Virtual screening using compound II yielded compounds with moderate Na(v)1.4 inactivated state block, but none surpassed compound II's activity.
• Compounds 2 and 16 represent potent clathrodin analogs and novel scaffolds for Na(v)1.7 modulator discovery.

Conclusions:

• Virtual screening effectively identified novel VGSC modulators.
• Compounds 2 and 16 are promising leads for developing human Na(v)1.7 channel modulators.