TY - JOUR
T1 - Identification of a novel chemical potentiator and inhibitors of UCH-L1 by in silico drug screening
AU - Mitsui, Takeshi
AU - Hirayama, Kazunori
AU - Aoki, Shunsuke
AU - Nishikawa, Kaori
AU - Uchida, Kenko
AU - Matsumoto, Takashi
AU - Kabuta, Tomohiro
AU - Wada, Keiji
PY - 2010/4
Y1 - 2010/4
N2 - Ubiquitin-C-terminal hydrolase L1 (UCH-L1) is a de-ubiquitinating enzyme expressed in the brain and reproductive tissues as well as certain cancers. The hydrolase activity of UCH-L1 has been implicated in Alzheimer's disease and cancer invasion; therefore, it may represent a therapeutic target for these diseases. The present study was undertaken to identify novel chemical modulators for the hydrolase activity of UCH-L1. To identify chemicals that bind to the active site of UCH-L1, we carried out in silico structure-based drug screening using human UCH-L1 crystal structure data (PDB ID: 2ETL) and virtual compound libraries containing 26,891 and 304,205 compounds. Among the compounds with the highest binding scores, we identified one that potentiates the hydrolase activity of UCH-L1, and six that inhibit the activity in enzymatic assays. These compounds may be useful for research on UCH-L1 function, and could lead to candidate therapeutics for UCH-L1-associated diseases.
AB - Ubiquitin-C-terminal hydrolase L1 (UCH-L1) is a de-ubiquitinating enzyme expressed in the brain and reproductive tissues as well as certain cancers. The hydrolase activity of UCH-L1 has been implicated in Alzheimer's disease and cancer invasion; therefore, it may represent a therapeutic target for these diseases. The present study was undertaken to identify novel chemical modulators for the hydrolase activity of UCH-L1. To identify chemicals that bind to the active site of UCH-L1, we carried out in silico structure-based drug screening using human UCH-L1 crystal structure data (PDB ID: 2ETL) and virtual compound libraries containing 26,891 and 304,205 compounds. Among the compounds with the highest binding scores, we identified one that potentiates the hydrolase activity of UCH-L1, and six that inhibit the activity in enzymatic assays. These compounds may be useful for research on UCH-L1 function, and could lead to candidate therapeutics for UCH-L1-associated diseases.
KW - Alzheimer's disease
KW - Cancer
KW - In silico
KW - Inhibitor
KW - Potentiator
KW - Ubiquitin-C-terminal hydrolase L1 (UCH-L1)
UR - http://www.scopus.com/inward/record.url?scp=77949570178&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77949570178&partnerID=8YFLogxK
U2 - 10.1016/j.neuint.2010.01.016
DO - 10.1016/j.neuint.2010.01.016
M3 - Article
C2 - 20144674
AN - SCOPUS:77949570178
VL - 56
SP - 679
EP - 686
JO - Neurochemistry International
JF - Neurochemistry International
SN - 0197-0186
IS - 5
ER -