化学
药效团
IC50型
立体化学
酶
活动站点
对接(动物)
组氨酸
结合位点
小分子
体外
分子动力学
生物化学
计算化学
医学
护理部
作者
Andrija Šmelcerović,Aleksandra Živković,Budimir S. Ilić,Ana Kolarević,Bettina Hofmann,Dieter Steinhilber,Holger Stark
标识
DOI:10.1016/j.bioorg.2019.103528
摘要
Eleven new 4-(4-chlorophenyl)thiazol-2-amines were synthesized and, together with nine known derivatives, evaluated in vitro for inhibitory properties towards bovine pancreatic DNase I. Three compounds (18–20) inhibited DNase I with IC50 values below 100 µM, with compound 19 being the most potent (IC50 = 79.79 µM). Crystal violet, used as a positive control in the absence of a “golden standard”, exhibited almost 5-fold weaker DNase I inhibition. Pharma/E-State RQSAR models clarified critical structural fragments relevant for DNase I inhibition. Molecular docking and molecular dynamics simulation defined the 4-(4-chlorophenyl)thiazol-2-amines interactions with the most important catalytic residues of DNase I. Ligand-based pharmacophore modeling and virtual screening confirmed the chemical features of 4-(4-chlorophenyl)thiazol-2-amines required for DNase I inhibition and proved the absence of structurally similar molecules in available databases. Compounds 18–20 have been shown as very potent 5-LO inhibitors with nanomolar IC50 values obtained in cell-free assay, with compound 20 being the most potent (IC50 = 50 nM). Molecular docking and molecular dynamics simulations into the binding site of 5-LO enzyme allowed us to clarify the binding mode of these dual DNase I/5-LO inhibitors. It was shown that compounds 18–20 uniquely show interactions with histidine residues in the catalytic site of DNase I and 5-LO enzyme. In the absence of potent organic DNase I inhibitors, compounds 18–20 represent a good starting point for the development of novel Alzheimer's therapeutics based on dual 5-LO and DNase I inhibition, which also have anti-inflammatory properties.
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