title: Identification of novel chemical inhibitors for ubiquitin C-terminal hydrolase-L3 by virtual screening.
abstract: UCH-L3 (ubiquitin C-terminal hydrolase-L3) is a de-ubiquitinating enzyme that is a component of the ubiquitin-proteasome system and known to be involved in programmed cell death. A previous study of high-throughput drug screening identified an isatin derivative as a UCH-L3 inhibitor. In this study, we attempted to identify a novel inhibitor with a different structural basis. We performed in silico structure-based drug design (SBDD) using human UCH-L3 crystal structure data (PDB code; 1XD3) and the virtual compound library (ChemBridge CNS-Set), which includes 32,799 chemicals. By a two-step virtual screening method using DOCK software (first screening) and GOLD software (second screening), we identified 10 compounds with GOLD scores of over 60. To address whether these compounds exhibit an inhibitory effect on the de-ubiquitinating activity of UCH-L3, we performed an enzymatic assay using ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) as the substrate. As a result, we identified three compounds with similar basic dihydro-pyrrole skeletons as UCH-L3 inhibitors. These novel compounds may be useful for the research of UCH-L3 function, and in drug development for UCH-L3-associated diseases.
authors.affiliation: Department of Electrical Engineering and Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Tokyo, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Hirayama
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Aoki
authors.forename: Kaori
authors.initials: K
authors.lastname: Nishikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
mesh_terms: D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D012984:Software; D013379:Substrate Specificity; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D005663:Furans; D011758:Pyrroles; D043222:Ubiquitin Thiolesterase