Schleifer K J
Heinrich-Heine-Universität Düsseldorf, Institute for Pharmaceutical Chemistry, Germany.
J Comput Aided Mol Des. 2000 Jul;14(5):467-75. doi: 10.1023/a:1008141819487.
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.
本文描述了一种用于调节兔骨骼肌中兰尼碱受体（RyR）的兰尼碱类化合物的假受体模型的构建。为此，应用分子建模软件PrGen将一组15种兰尼碱衍生物的实验测定结合自由能与计算结合自由能进行关联。最终模型显示，一个具有氢键供体和受体能力（由一个天冬酰胺表示）的狭窄裂缝对于结合兰尼碱C3位的吡咯羧酸取代基最为关键。此外，芳香吡咯环两侧为疏水残基（酪氨酸、苯丙氨酸和异亮氨酸）。其中两个残基（酪氨酸和异亮氨酸）与2-异丙基部分相互作用，这似乎有助于结合。与吡咯位点相对，第二个疏水区域（由一个亮氨酸表示）在纵向轴上限制兰尼碱衍生物，并导致对C9位赤道和轴向甲基以及极性取代基的区分。最后，一个带电荷的谷氨酸残基与C10和C15位的羟基形成强氢键和静电相互作用。对于这个由六个氨基酸残基组成的结合位点模型，得到了训练集配体的相关系数R = 0.99（Q2 = 0.975），并且在预测四个测试集配体的结合能时，均方根（rms）偏差为0.568 kcal/mol。基于这个假受体模型，将讨论兰尼碱类化合物实际结合位点的推测拓扑结构。
