Henan University of Chinese Medicine, Zhengzhou, 450046, Henan, China.
Department of Applied Chemistry, Zhengzhou University of Light Industry, Zhengzhou, 450002, Henan, China.
Sci Rep. 2020 Nov 23;10(1):20415. doi: 10.1038/s41598-020-77399-y.
Catalpol has gained increasing attention for its potential contributions in controlling glycolipid metabolism and diabetic complications, which makes used as a very promising scaffold for seeking new anti-diabetic drug candidates. Acylation derivatives of catalpol crotonate (CCs) were designed as drug ligands of glutathione peroxidase (GSH-Px) based on molecular docking (MD) using Surfex-Docking method. Catalpol hexacrotonate (CC-6) was synthesized using microwave assisted method and characterized by FT-IR, NMR, HPLC and HRMS. The MD results indicate that with the increasing of esterification degree of hydroxyl, the C log P of CCs increased significantly, and the calculated total scores (Total_score) of CCs are all higher than that of catalpol. It shows that CCs maybe served as potential lead compounds for neuroprotective agents. It was found that the maximum Total_score of isomers in one group CCs is often not that the molecule with minimum energy. MD calculations show that there are five hydrogen bonds formed between CC-6 and the surrounding amino acid residues. Molecular dynamics simulation results show that the binding of CC-6 with GSH-Px is stable. CC-6 was screened for SH-SY5Y cells viability by MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay, the result indicates CC-6 can effectively reverse SZT induced cells apoptosis with dose-dependent manner, which can indirectly show that CC-6 is a potential neuroprotective agent.
梓醇由于其在控制糖脂代谢和糖尿病并发症方面的潜在作用而受到越来越多的关注，使其成为寻找新型抗糖尿病药物候选物的非常有前途的支架。基于分子对接（MD）方法，使用 Surfex-Docking 方法，将梓醇巴豆酸酯（CCs）设计为谷胱甘肽过氧化物酶（GSH-Px）的药物配体。使用微波辅助方法合成梓醇六巴豆酸酯（CC-6），并通过 FT-IR、NMR、HPLC 和 HRMS 进行表征。MD 结果表明，随着羟基酯化程度的增加，CCs 的 C log P 显著增加，并且 CCs 的计算总得分（Total_score）均高于梓醇。这表明 CCs 可能作为神经保护剂的潜在先导化合物。结果发现，一组 CCs 中异构体的最大总得分通常不是能量最小的分子。MD 计算表明，CC-6 与周围氨基酸残基之间形成了五个氢键。分子动力学模拟结果表明，CC-6 与 GSH-Px 的结合是稳定的。通过 MTT（3-(4,5-二甲基噻唑基-2)-2,5-二苯基四唑溴盐）测定法筛选 CC-6 对 SH-SY5Y 细胞活力的影响，结果表明 CC-6 可以有效逆转 SZT 诱导的细胞凋亡，呈剂量依赖性，这可以间接表明 CC-6 是一种潜在的神经保护剂。
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