Discovery of Novel Bruton's Tyrosine Kinase Inhibitors Using a Hybrid Protocol of Virtual Screening Approaches Based on SVM Model, Pharmacophore and Molecular Docking

Abstract

Bruton's tyrosine kinase has emerged as a potential target for the treatment for B-cell malignancies and autoimmune diseases. Discovery of Bruton's tyrosine kinase inhibitors has thus attracted much attention recently. In this investigation, we introduced a hybrid protocol of virtual screening methods including support vector machine model-based virtual screening, pharmacophore model-based virtual screening and docking-based virtual screening for retrieving new Bruton's tyrosine kinase inhibitors from commercially available chemical databases. Performances of the hybrid virtual screening approach were evaluated against a test set, which results showed that the hybrid virtual screening approach significantly shortened the overall screening time, and considerably increased the hit rate and enrichment factor compared with the individual method (SB-VS, PB-VS and DB-VS) or their combinations by twos. This hybrid virtual screening approach was then applied to screen several chemical databases including Specs (202408 compounds) and Enamine (980000 compounds) databases. Thirty-nine compounds were selected from the final hits and have been shifted to experimental studies. Bruton's tyrosine kinase (BTK) has emerged as a potential target for the treatment of B-cell malignancies and autoimmune diseases. We introduced a hybrid protocol of virtual screening (VS) methods including support vector machine model-based VS (SB-VS), pharmacophore model-based (PB-VS), and docking-based VS (DB-VS) for retrieving new BTK inhibitors from commercially available chemical databases. Thirty-nine compounds were selected from the final hits and have been shifted to the subsequent experimental studies. © 2012 John Wiley & Sons A/S.