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

Abstract

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.

Keywords:

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

Acknowledgements

The authors wish to thank Dr A.K. Tiwary, Head of the Department of Pharmaceutical Science and Drug Research, Punjabi University, Patiala, for his helpful collaboration and valuable advice. We are also grateful to AICTE for providing a fellowship.