Sever Belgin, Kucukoglu Kaan, Nadaroglu Hayrunnisa, Altıntop Mehlika Dilek
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskisehir, Turkey.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Bulent Ecevit University, Zonguldak, Turkey.
Curr Comput Aided Drug Des. 2019;15(2):136-144. doi: 10.2174/1573409914666180518085908.
Paraoxonase 1 (PON1) is a paraoxonase, arylesterase and lactonase associated with protection of lipoproteins and cell membranes against oxidative modification.
Based on antioxidative properties of PON1 and significance of 1,3,4-thiadiazoles in pharmaceutical chemistry, herein we aimed to evaluate the potentials of 1,3,4-thiadiazole derivatives as PON1 activators.
2-[[5-(2,4-Difluoro/dichlorophenylamino)-1,3,4-thiadiazol-2-yl]thio]acetophenone derivatives (1-18) were in vitro evaluated for their activator effects on PON1 which was purified using ammonium sulfate precipitation (60-80%) and DEAE-Sephadex anion exchange chromatography. Molecular docking studies were performed for the detection of affinities of all compounds to the active site of PON1. Moreover, Absorption, Distribution, Metabolism and Excretion (ADME) properties of all compounds were also in silico predicted. In silico molecular docking and ADME studies were carried out according to modules of Schrodinger's Maestro molecular modeling package.
All compounds, particularly compounds 10, 13 and 17, were determined as promising PON1 activators and apart from compound 1, all of them were detected in the active site of PON1. Besides, ADME results indicated that all compounds were potential orally bioavailable drug-like molecules.
PON1 activators, compounds 10, 13 and 17 stand out as potential drug candidates for further antioxidant studies and these compounds can be investigated for their therapeutic effects in many disorders such as atherosclerosis, diabetes mellitus, obesity, chronic liver inflammation and many more.
对氧磷酶1（PON1）是一种对氧磷酶、芳基酯酶和内酯酶，与保护脂蛋白和细胞膜免受氧化修饰有关。
基于PON1的抗氧化特性以及1,3,4-噻二唑在药物化学中的重要性，我们旨在评估1,3,4-噻二唑衍生物作为PON1激活剂的潜力。
体外评估2-[[5-(2,4-二氟/二氯苯基氨基)-1,3,4-噻二唑-2-基]硫代]苯乙酮衍生物（1-18）对PON1的激活作用，该PON1通过硫酸铵沉淀（60-80%）和DEAE-葡聚糖阴离子交换色谱法纯化。进行分子对接研究以检测所有化合物对PON1活性位点的亲和力。此外，还通过计算机模拟预测了所有化合物的吸收、分布、代谢和排泄（ADME）特性。根据薛定谔公司的Maestro分子建模软件包的模块进行计算机模拟分子对接和ADME研究。
所有化合物，特别是化合物10、13和17，被确定为有前景的PON1激活剂，除化合物1外，所有化合物都在PON1的活性位点被检测到。此外，ADME结果表明所有化合物都是具有潜在口服生物利用度的类药物分子。
PON1激活剂化合物10、13和17作为进一步抗氧化研究的潜在药物候选物脱颖而出，这些化合物可针对动脉粥样硬化、糖尿病、肥胖症、慢性肝脏炎症等多种疾病的治疗效果进行研究。
