title: 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 (202,408 compounds) and Enamine (980,000 compounds) databases. Thirty-nine compounds were selected from the final hits and have been shifted to experimental studies.
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, China.
authors.forename: Hua-Lin
authors.initials: HL
authors.lastname: Wan
authors.forename: Ze-Rong
authors.initials: ZR
authors.lastname: Wang
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Li
authors.forename: Chuan
authors.initials: C
authors.lastname: Cheng
authors.forename: Pan
authors.initials: P
authors.lastname: Ji
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Liu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Zou
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D060388:Support Vector Machine
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase