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

• Published in: SAR and QSAR in environmental research 2011-03, Vol.22 (1-2), p.171-190
• Main Authors: Bagga, V., Silakari, O., Ghorela, V.S., Bahia, M.S., Rambabu, G., Sarma, J.
• Format: Article
• Language: English
• Subjects: Fischer's test; Interleukin-2-inducible T-cell kinase; Models, Chemical; Models, Molecular; pharmacophore; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - metabolism; Structure-Activity Relationship; tyrosine kinase; virtual screening
• ISSN: 1062-936X; 1029-046X
• DOI: 10.1080/1062936X.2010.510480

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 r 2 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.