Department of Pharmacy, College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon, Republic of Korea.
J Biomol Struct Dyn. 2024 Sep;42(14):7128-7149. doi: 10.1080/07391102.2023.2238068. Epub 2023 Jul 21.
We aimed to further explore the relationship between heterocyclic molecules and their associated biological activities for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. A dataset of 36 heterocycles was used to predict the activity of AChE and BChE inhibitors (the pIC50 values ranged from 7.84 to 12.49). A quantitative structure-activity relationship (QSAR) study was generated with the help of four different models (BMA, MNLR, MLR, and ANN). Four of the models were statistically acceptable based on both internal and external validation. The descriptors used in the models were similar to the X-ray structures of the target-ligand complexes, which made it possible to predict the pIC50 for AChE and BChE enzymes. Five selected molecules (compounds 6 (CHFNO), compound 7 (CHFNO), and compound 8 (CHFNO) belong to the oxadiazole derivative group; compound 16 (CHClNO) is classified into the chemical structures of different N, O, and S-based heterocycle groups; and compound 25 (CHNO) pertains to the pyrimidine derivative group) possessed high pIC50 values for AChE and BChE enzymes (pIC50 values for AChE and BChE ranged from 9.01 to 10.32). The range of docking scores between the AChE and BChE receptors and their respective candidates was from -8.1 to -9.2 kcal/mol. The pharmacokinetics, biological activities, and physicochemical properties of five selected compounds supported their ability to protect against AD because they are not toxic, have a cholinergic effect, can cross the blood-brain barrier, and are well absorbed by the gastrointestinal tract.Communicated by Ramaswamy H. Sarma.
我们旨在进一步探讨杂环分子与乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）酶相关生物活性之间的关系。使用 36 个杂环数据集来预测 AChE 和 BChE 抑制剂的活性（pIC50 值范围为 7.84 至 12.49）。借助四个不同模型（BMA、MNLR、MLR 和 ANN）进行了定量构效关系（QSAR）研究。四个模型基于内部和外部验证均具有统计学意义。模型中使用的描述符与靶标-配体复合物的 X 射线结构相似，这使得可以预测 AChE 和 BChE 酶的 pIC50。选择了五个分子（化合物 6（CHFNO）、化合物 7（CHFNO）和化合物 8（CHFNO）属于噁二唑衍生物组；化合物 16（CHClNO）归类为不同的 N、O 和 S 基杂环化学结构组；化合物 25（CHNO）属于嘧啶衍生物组）对 AChE 和 BChE 酶具有较高的 pIC50 值（AChE 和 BChE 的 pIC50 值范围为 9.01 至 10.32）。AChE 和 BChE 受体与其各自候选物之间的对接评分范围为-8.1 至-9.2 kcal/mol。五个选定化合物的药代动力学、生物活性和物理化学性质支持它们具有预防 AD 的能力，因为它们没有毒性、具有胆碱能作用、可以穿过血脑屏障并且被胃肠道很好地吸收。由 Ramaswamy H. Sarma 传达。
