Pagadala Nataraj S, Perez-Pineiro Rolando, Wishart David S, Tuszynski Jack A
Department of Medical Microbiology and Immunology, 6-020 Katz Group Centre, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
Departments of Biological Sciences, and Computing Science, University of Alberta, Edmonton, Alberta T6G 2E8, Canada.
Eur J Med Chem. 2015 Feb 16;91:118-31. doi: 10.1016/j.ejmech.2014.07.045. Epub 2014 Jul 15.
To understand the pharmacophore properties of 2-aminothiazoles and design novel inhibitors against the prion protein, a highly predictive 3D quantitative structure-activity relationship (QSAR) has been developed by performing comparative molecular field analysis (CoMFA) and comparative similarity analysis (CoMSIA). Both CoMFA and CoMSIA maps reveal the presence of the oxymethyl groups in meta and para positions on the phenyl ring of compound 17 (N-[4-(3,4-dimethoxyphenyl)-1,3-thiazol-2-yl]quinolin-2-amine), is necessary for activity while electro-negative nitrogen of quinoline is highly favorable to enhance activity. The blind docking results for these compounds show that the compound with quinoline binds with higher affinity than isoquinoline and naphthalene groups. Out of 150 novel compounds retrieved using finger print analysis by pharmacophoric model predicted based on five test sets of compounds, five compounds with diverse scaffolds were selected for biological evaluation as possible PrP inhibitors. Molecular docking combined with fluorescence quenching studies show that these compounds bind to pocket-D of SHaPrP near Trp145. The new antiprion compounds 3 and 6, which bind with the interaction energies of -12.1 and -13.2 kcal/mol, respectively, show fluorescence quenching with binding constant (Kd) values of 15.5 and 44.14 μM, respectively. Further fluorescence binding assays with compound 5, which is similar to 2-aminothiazole as a positive control, also show that the molecule binds to the pocket-D with the binding constant (Kd) value of 84.7 μM. Finally, both molecular docking and a fluorescence binding assay of noscapine as a negative control reveals the same binding site on the surface of pocket-A near a rigid loop between β2 and α2 interacting with Arg164. This high level of correlation between molecular docking and fluorescence quenching studies confirm that these five compounds are likely to act as inhibitors for prion propagation while noscapine might act as a prion accelerator from PrP(C) to PrP(Sc).
为了解2-氨基噻唑的药效团特性并设计针对朊病毒蛋白的新型抑制剂，通过进行比较分子场分析（CoMFA）和比较相似性分析（CoMSIA），开发了一种高度预测性的三维定量构效关系（QSAR）。CoMFA和CoMSIA图谱均显示，化合物17（N-[4-(3,4-二甲氧基苯基)-1,3-噻唑-2-基]喹啉-2-胺）苯环间位和对位的氧甲基基团的存在对活性是必需的，而喹啉的电负性氮对增强活性非常有利。这些化合物的盲对接结果表明，含喹啉的化合物比异喹啉和萘基团具有更高的亲和力。在基于五组化合物测试集预测的药效团模型通过指纹分析检索到的150种新型化合物中，选择了五种具有不同骨架的化合物作为可能的朊病毒蛋白抑制剂进行生物学评估。分子对接结合荧光猝灭研究表明，这些化合物与SHaPrP的口袋-D结合，靠近色氨酸145。新型抗朊病毒化合物3和6分别以-12.1和-13.2 kcal/mol的相互作用能结合，分别显示出结合常数（Kd）值为15.5和44.14 μM的荧光猝灭。用与2-氨基噻唑相似的化合物5作为阳性对照进行的进一步荧光结合试验也表明，该分子以84.7 μM的结合常数（Kd）值与口袋-D结合。最后，作为阴性对照的那可丁的分子对接和荧光结合试验均揭示了口袋-A表面上靠近β2和α2之间刚性环与精氨酸164相互作用的相同结合位点。分子对接和荧光猝灭研究之间的这种高度相关性证实，这五种化合物可能作为朊病毒传播的抑制剂，而那可丁可能作为从PrP(C)到PrP(Sc)的朊病毒促进剂。
