Pseudoreceptor model for ryanodine derivatives at calcium release channels

Area of Science:

• Pharmacology
• Molecular Biology
• Computational Chemistry

Background:

• Ryanodine receptors (RyRs) are critical calcium channels in muscle.
• Understanding RyR modulators (ryanoids) is vital for treating muscle disorders.
• Existing models lack detailed binding site information for ryanoids.

Purpose of the Study:

• To generate a pseudoreceptor model for ryanodine receptor (RyR) modulating ryanoids.
• To correlate experimental binding energies with calculated values for ryanoid derivatives.
• To elucidate key molecular interactions governing ryanoid binding to RyRs.

Main Methods:

• Application of the PrGen molecular modeling software.
• Correlation of experimentally determined and calculated free energies of binding.
• Analysis of 15 ryanodine derivatives to build the binding site model.

Main Results:

• Identified a narrow cleft with hydrogen bond donors/acceptors (Asn) crucial for C3 pyrrole carboxylate binding.
• Discovered hydrophobic residues (Tyr, Phe, Ile) flanking the pyrrole ring and interacting with the 2-isopropyl moiety.
• Revealed a second hydrophobic region (Leu) restricting ligand orientation and discriminating C9 substituents.
• Observed strong hydrogen bonding and electrostatic interactions with glutamate at C10 and C15 hydroxyl groups.
• Achieved high correlation (R=0.99, Q2=0.975) and low prediction error (rms=0.568 kcal/mol).

Conclusions:

• The developed pseudoreceptor model accurately predicts ryanoid binding energies.
• Key amino acid residues and their interactions within the RyR binding site were identified.
• The model provides insights into the putative topology of the real ryanoid binding site.
• This work facilitates the design of novel RyR modulators with improved efficacy and specificity.