title: Pseudoreceptor model for ryanodine derivatives at calcium release channels.
abstract: This paper describes the generation of a pseudoreceptor model for ryanodine receptor (RyR) modulating ryanoids in rabbit skeletal muscle. For this purpose, the molecular modelling software PrGen was applied to correlate experimentally determined and calculated free energies of binding for a set of 15 ryanodine derivatives. The final model indicates a narrow cleft with hydrogen bond donor and acceptor capacities (represented by an Asn) as most crucial for binding the pyrrole carboxylate substituent at C3 of ryanodine. In addition, hydrophobic residues flank the aromatic pyrrole ring (Tyr, Phe, and Ile). Two of those residues (Tyr and Ile) interact with the 2-isopropyl moiety, which seems to contribute to binding. Opposite to the pyrrole locus, a second hydrophobic region (represented by a Leu) restricts ryanodine derivatives in their longitudinal axis and leads to the discrimination of equatorial and axial positioned methyl groups and of polar substituents at C9. Finally, a charged glutamate residue generates strong hydrogen bonding and electrostatic interactions with the hydroxyl groups at C10 and C15. For this binding-site model--composed of six amino acid residues--a correlation for the training set ligands of R = 0.99 (Q2 = 0.975) and a root mean square (rms) deviation of 0.568 kcal/mol for the prediction of the binding energies of four test set ligands was obtained. Based on this pseudoreceptor model the putative topology of the real binding site of ryanoids will be discussed.
authors.affiliation: Heinrich-Heine-Universität Düsseldorf, Institute for Pharmaceutical Chemistry, Germany. kjs@pharm.uni-duesseldorf.de
authors.forename: K J
authors.initials: KJ
authors.lastname: Schleifer
mesh_terms: D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D017076:Computer-Aided Design; D015195:Drug Design; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects; D011487:Protein Conformation; D011817:Rabbits; D012433:Ryanodine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000187:drug effects*
chemical_list: D008024:Ligands; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine