Peng Youyi, Keenan Susan M, Zhang Qiang, Welsh William J
Department of Pharmacology, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School (UMDNJ-RWJMS), and the Informatics Institute of UMDNJ, Piscataway, NJ 08854, USA.
J Mol Graph Model. 2005 Sep;24(1):25-33. doi: 10.1016/j.jmgm.2005.05.001.
Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were constructed using comparative molecular field analysis (CoMFA) for a series of delta opioid receptor agonists: SNC80 analogs. Quantum chemical calculations on SNC80 show that protonation is preferred at the basic N4 atom over the alternative N1 atom, accordingly N4 protonation may contribute significantly to ligand-receptor interactions under physiologically relevant conditions. Statistically significant and predictive CoMFA models were achieved by pooling biological data from independent published sources, including compounds with both alphaR and alphaS benzylic configurations. Improved CoMFA models were obtained when the compounds were considered as N4-protonated species rather than neutral compounds. The influence of various atomic partial-charge formalisms, alignment schemes and additional molecular descriptors was evaluated in order to produce the highest quality models. In addition, separate CoMFA models were generated for compounds with only the alphaR benzylic configuration. These CoMFA models showed excellent internal predictability and consistency, and external validation using test-set compounds yielded predicted pIC50 values within 1log unit of the corresponding experimentally measured values. Key insights into the structure-activity relationship derived from the CoMFA analysis concur with experimentally observed data, thus the CoMFA models presented here find utility for predicting the binding affinity, and guiding the design, of novel SNC80 analogs and related delta opioid receptor agonists.
利用比较分子场分析（CoMFA）构建了一系列δ阿片受体激动剂：SNC80类似物的三维定量构效关系（3D-QSAR）模型。对SNC80的量子化学计算表明，在生理相关条件下，碱性的N4原子比另一个N1原子更易质子化，因此N4质子化可能对配体-受体相互作用有显著贡献。通过汇总来自独立已发表来源的生物学数据，包括具有αR和αS苄基构型的化合物，获得了具有统计学意义和预测性的CoMFA模型。当将化合物视为N4质子化物种而非中性化合物时，得到了改进的CoMFA模型。评估了各种原子部分电荷形式、对齐方案和其他分子描述符的影响，以生成最高质量的模型。此外，还为仅具有αR苄基构型的化合物生成了单独的CoMFA模型。这些CoMFA模型显示出出色的内部预测性和一致性，使用测试集化合物进行的外部验证产生的预测pIC50值与相应的实验测量值相差在1个对数单位内。从CoMFA分析得出的构效关系的关键见解与实验观察数据一致，因此本文提出的CoMFA模型可用于预测新型SNC80类似物和相关δ阿片受体激动剂的结合亲和力，并指导其设计。
