title: Pharmacophore modeling and hybrid virtual screening for the discovery of novel IκB kinase 2 (IKK2) inhibitors.
abstract: IKK2 (IκB kinase 2) inhibitors have been identified as potential drug candidates in the treatment of various immune/inflammatory disorders as well as cancer. So far more than one hundred small molecule inhibitors against IKK2 have been reported publicly. In this investigation, pharmacophore modeling was carried out to clarify the essential structure-activity relationship for the known IKK2 inhibitors. One of the established pharmacophore hypotheses, namely Hypo8, which has the best prediction ability to an external test data set, was suggested as a template for virtual screening. Evaluation of the performances of Hypo8 and a hybrid method (Hypo81docking) in virtual screening indicated that the use of the hybrid virtual screening considerably increased the hit rate and enrichment factor. The hybrid method was therefore adopted for screening several commercially available chemical databases, including Specs, NCI, Maybridge and Chinese Nature Product Database (CNPD), for novel potent IKK2 inhibitors. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five. Finally some of the final hit compounds were selected and suggested for further experimental investigations.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, No. 1, Keyuan Rd. 4, Gaopeng Avenue, High Tech Park, Chengdu, Sichuan 610041, China.
authors.forename: Huan-Zhang
authors.initials: HZ
authors.lastname: Xie
authors.forename: Ling-Yun
authors.initials: LY
authors.lastname: Liu
authors.forename: Ji-Xia
authors.initials: JX
authors.lastname: Ren
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Zhou
authors.forename: Ren-Lin
authors.initials: RL
authors.lastname: Zheng
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Li
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008962:Models, Theoretical; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D051550:I-kappa B Kinase