Phenylalkylamines in calcium channels: computational analysis of experimental structures

Area of Science:

• Structural Biology
• Pharmacology
• Computational Chemistry

Background:

• Phenylalkylamines (PAAs) are critical cardiovascular drugs targeting calcium channels.
• Existing 3D structures of calcium channels bound to PAAs show ligand binding in the inner pore, but with notable differences.
• Understanding the atomic-level interactions is crucial for drug development.

Purpose of the Study:

• To investigate the binding mechanisms of PAAs within calcium channels using computational methods.
• To reconcile discrepancies observed between different experimental structures of calcium channels with PAAs.
• To elucidate the atomic basis for structure-activity relationships of PAAs.

Main Methods:

• Monte Carlo energy minimizations were employed to dock PAAs into calcium channel models.
• Analysis of published crystal and cryo-electron microscopy (cryo-EM) structures.
• Computational modeling of Cav1.2 channels with various PAAs.

Main Results:

• Docking simulations suggest a water molecule, not a calcium ion, occupies Site 3 in the crystal structure.
• Simulations reproduced observed binding modes of verapamil in cryo-EM structures, including shifts relative to the calcium ion.
• Removing detergent and lipid molecules in cryo-EM models allowed the verapamil nitrile group to bind the calcium ion at Site 3.
• Models of Cav1.2 with different PAAs indicate similar binding modes and direct interactions with the calcium ion at Site 3.

Conclusions:

• The study provides a computational framework to understand PAA binding in calcium channels.
• Observed interactions between PAAs and calcium ions at Site 3 explain previously paradoxical structure-activity relationships.
• These findings offer insights into the mechanism of action for PAA cardiovascular drugs.