A three-dimensional pharmacophore modelling of ITK inhibitors and virtual screening for novel inhibitors

作者：Bagga V; Silakari O^*; Ghorela V S; Bahia M S; Rambabu G; Sarma J

来源：SAR and QSAR in Environmental Research, 2011, 22(1-2): 171-190.

DOI：10.1080/1062936X.2010.510480

• Interleukin-2-inducible T-cell kinase
• pharmacophore
• Fischer's test
• virtual screening
• tyrosine kinase

Interleukin-2-inducible T-cell kinase (ITK) is a key member of the Tec family of non-receptor tyrosine kinases, and has been found to be a novel target for a number of inflammatory and autoimmune diseases. A three-dimensional pharmacophore model has been generated for protein ITK from its known inhibitors. The best HypoGen model consisted of four pharmacophore features: one hydrogen bond acceptor, one hydrogen bond donor and two hydrophobic rings. This model showed a correlation coefficient of 0.947, a root mean square deviation of 0.914 and a configuration cost of 16.866. The model was validated using test set prediction and Fischer's test. A test set containing 204 compounds showed an r2 of 0.745 between estimated activity and activity measured experimentally. Fisher's test gave a confidence level of 95%. The best pharmacophore model (Hypo1) was then employed for virtual screening (3D database searching), including Lipinsiki's filter, to obtain a pool of more drug-like molecules. The molecular pool thus retrieved was subjected to docking analysis with a study protein to remove any molecules showing false positive activity for ITK.

• 出版日期2011