QSAR of Flavonoids: 4. Differential Inhibition of Aldose Reductase and p56~(lck) Protein Tyrosine Kinase

摘要

Flavonoids are a group of low molecular weight plant products, based on the parent compound, flavone (2-phenylchromone) and have shown potential for application in a variety of pharmacological targets. By using random screening techniques flavones have been proposed as inhibitors of aldose reductase, an enzyme crucial in the treatment of diabetic complications such as cataract formation. On the other hand, a large number of natural and synthetic flavo-noids are being tested as specific inhibitors of protein tyrosine ki-nase (PTK). Kinetic analyses of the PTK inhibition indicate that flavonoids are competitive inhibitors with respect to the nucleotide ATP. A thorough investigation of the available experimental data base by using both classical and quantum chemical descriptors has been performed in order to develop quantitative structure-activity relationships for these enzyme systems. Relevance of the descriptors to binding properties of both enzyme receptors active site is proposed and the obtained results demonstrate in detail which specific electronic as well as the hydrophobic and steric properties of the substituents play a significant role in their differential binding.