title: Protein Flexibility in Docking-Based Virtual Screening: Discovery of Novel Lymphoid-Specific Tyrosine Phosphatase Inhibitors Using Multiple Crystal Structures.
abstract: Incorporating protein flexibility is a major challenge for docking-based virtual screening. With an increasing number of available crystal structures, ensemble docking with multiple protein structures is an efficient approach to deal with protein flexibility. Herein, we report the successful application of a docking-based virtual screen using multiple crystal structures to discover novel inhibitors of lymphoid-specific tyrosine phosphatase (LYP), a potential drug target for autoimmune diseases. The appropriate use of multiple protein structures allowed a better enrichment than a single structure in the recovery of known inhibitors. Subsequently, an optimal ensemble of LYP structures was selected and used in docking-based virtual screening. Eight novel LYP inhibitors (IC50 ranging from 7.95 to 56.6 μM) were identified among 23 hit compounds. Further studies demonstrated that the most active compound B15 possessed some selectivity over other protein phosphatases and could effectively up-regulate TCR (T cell receptor)-mediated signaling in Jurkat T cells. These novel hits not only provided good starting points for the development of therapeutic agents useful in autoimmune diseases but also demonstrated the advantages of choosing an appropriate ensemble of protein structures in docking-based virtual screening over using a single protein conformation.
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, ‡Department of Physiology, School of Medicine, and §Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University , Jinan, Shandong 250012, China.
authors.forename: Xuben
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, ‡Department of Physiology, School of Medicine, and §Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University , Jinan, Shandong 250012, China.
authors.forename: Kangshuai
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, ‡Department of Physiology, School of Medicine, and §Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University , Jinan, Shandong 250012, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, ‡Department of Physiology, School of Medicine, and §Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University , Jinan, Shandong 250012, China.
authors.forename: Jin-peng
authors.initials: JP
authors.lastname: Sun
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, ‡Department of Physiology, School of Medicine, and §Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University , Jinan, Shandong 250012, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Fang
mesh_terms: D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22