3D QSAR AND MOLECULAR DOCKING STUDIES OF FLAVONOIDS AS SPLEEN TYROSINE KINASE INHIBITORSAbstract
Spleen tyrosine kinase (Syk) is a member of tyrosine kinase family protein. Syk protein plays a vital role during intracellular signal transduction from high affinity IgE receptor (FcεRI) in allergic reaction. Flavonoids are well known compounds for their anti-allergic properties. In this present work, thirty-four structurally similar flavonoids are investigated as Syk inhibitors by using 3-dimensional quantitative structure-activity relationship (QSAR) models and molecular docking studies. By applying genetic algorithm (GA) method, different types of 3D-MoRSE descriptors are selected from various types of geometrical descriptors for model building. A Multiple Linear Regression is built up, considering the inhibitory effect of seventeen flavonoids on model mast cells by QSARINS software. The model is validated internally using the Q2 LOO criterion in leave-one-out method. William graph and Insubria graph are plotted to identify the application domain for that model. The same model is also externally validated for other seventeen flavonoid compounds. Docking studies of these thirty-four compounds are also performed using AutoDock to identify interacting amino acids of Syk protein. Docking analysis reveals that flavonoid chrysin depicts lowest binding energy, -2.74 with Syk protein. Methoxy substitution causes adverse effect on binding. The flavonoid chrysin is found in carrot. Pharmacokinetics study of chrysin shows that the gastrointestinal absorption of chrysin is high with bioavailability score of 0.55. The current work will help in drug design of human Syk inhibitors and provides information for molecular level of interactions between Syk and the flavonoid group of compounds.