Department of Medicinal Chemistry, P.O. Box 980540, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0540, USA.
J Mol Graph Model. 2010 Apr;28(7):612-25. doi: 10.1016/j.jmgm.2009.12.008. Epub 2010 Jan 4.
The highly potent and kappa-opioid (KOP) receptor-selective hallucinogen Salvinorin A and selected analogs have been analyzed using the 3D quantitative structure-affinity relationship technique Comparative Molecular Field Analysis (CoMFA) in an effort to derive a statistically significant and predictive model of salvinorin affinity at the KOP receptor and to provide additional statistical support for the validity of previously proposed structure-based interaction models. Two CoMFA models of Salvinorin A analogs substituted at the C-2 position are presented. Separate models were developed based on the radioligand used in the kappa-opioid binding assay, [(3)H]diprenorphine or [(125)I]6 beta-iodo-3,14-dihydroxy-17-cyclopropylmethyl-4,5 alpha-epoxymorphinan ([(125)I]IOXY). For each dataset, three methods of alignment were employed: a receptor-docked alignment derived from the structure-based docking algorithm GOLD, another from the ligand-based alignment algorithm FlexS, and a rigid realignment of the poses from the receptor-docked alignment. The receptor-docked alignment produced statistically superior results compared to either the FlexS alignment or the realignment in both datasets. The [(125)I]IOXY set (Model 1) and [(3)H]diprenorphine set (Model 2) gave q(2) values of 0.592 and 0.620, respectively, using the receptor-docked alignment, and both models produced similar CoMFA contour maps that reflected the stereoelectronic features of the receptor model from which they were derived. Each model gave significantly predictive CoMFA statistics (Model 1 PSET r(2)=0.833; Model 2 PSET r(2)=0.813). Based on the CoMFA contour maps, a binding mode was proposed for amine-containing Salvinorin A analogs that provides a rationale for the observation that the beta-epimers (R-configuration) of protonated amines at the C-2 position have a higher affinity than the corresponding alpha-epimers (S-configuration).
高活性和 κ 阿片受体（KOP）选择性致幻剂 Salvinorin A 及其选定的类似物已使用 3D 定量构效关系技术比较分子场分析（CoMFA）进行分析，旨在得出 KOP 受体上 Salvinorin 亲和力的统计学上显著和可预测的模型，并为先前提出的基于结构的相互作用模型的有效性提供额外的统计支持。呈现了两种取代 C-2 位置的 Salvinorin A 类似物的 CoMFA 模型。分别基于在 κ 阿片受体结合测定中使用的放射性配体开发了单独的模型，即[(3)H]二苯并庚烷或[(125)I]6β-碘-3,14-二羟基-17-环丙基甲基-4,5α-环氧吗啡烷([(125)I]IOXY)。对于每个数据集，使用了三种对齐方法：一种是来自基于结构的对接算法 GOLD 的受体对接对齐，另一种是来自基于配体的对齐算法 FlexS 的对齐，以及一种来自受体对接对齐的刚性重新对齐。在两个数据集的受体对接对齐产生了比 FlexS 对齐或重新对齐更优越的统计学结果。[(125)I]IOXY 集（模型 1）和[(3)H]二苯并庚烷集（模型 2）在使用受体对接对齐时分别给出了 q(2)值 0.592 和 0.620，两个模型都产生了相似的 CoMFA 等高线图，反映了它们从中衍生出的受体模型的立体电子特征。每个模型都给出了显著的可预测 CoMFA 统计数据（模型 1 PSET r(2)=0.833；模型 2 PSET r(2)=0.813）。基于 CoMFA 等高线图，提出了含胺 Salvinorin A 类似物的结合模式，为观察到 C-2 位置质子化胺的β-差向异构体（R-构型）比相应的α-差向异构体（S-构型）具有更高的亲和力提供了合理的解释。
