Journal
BIOORGANIC CHEMISTRY
Volume 95, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2019.103528
Keywords
DNase I; 5-Lipoxygenase; Inhibition; Molecular dynamics; Pharmacophore modeling; Alzheimer
Funding
- Ministry of Education, Science and Technological Development of the Republic of Serbia [OI 172044, OI 171025]
- Faculty of Medicine of the University of Nis [4]
- EU COST Action [13135]
- Alexander von Humboldt Foundation, Bonn, Germany
- HHU Funds for International Relationships
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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 mu M, with compound 19 being the most potent (IC50 = 79.79 mu M). 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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