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Identifying de‐NEDDylation inhibitors: Virtual high‐throughput screens targeting SENP8
Author(s) -
Chen Jonathan J.,
Schmucker Lyndsey N.,
Visco Donald P.
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13457
Subject(s) - high throughput screening , virtual screening , throughput , neddylation , yield (engineering) , computational biology , chemistry , microbiology and biotechnology , biology , drug discovery , computer science , biochemistry , ubiquitin , gene , materials science , telecommunications , ubiquitin ligase , metallurgy , wireless
Protein modification can have far‐reaching effects. NEDD ylation, a protein modification process with the protein NEDD 8, stabilizes and modifies how the targeted protein interacts with other proteins. Its role in system regulation makes it a prime therapeutic target, and virtual high‐throughput screening has already identified new NEDD 8 inhibitors. SENP 8 matures the NEDD 8 proenzyme into the active form and regulates NEDD ylation by removing NEDD 8 from over‐ NEDD ylated proteins. In this work, SENP 8 inhibitor candidates were identified in two rounds of virtual high‐throughput screening. Of the ten candidates identified in the first round of screening, four were active in validation experiments to yield an experimental hit rate of 40%. Of the five candidates identified in the second round of screening, one was active in validation experiments to yield an experimental hit rate of 20%. Results indicate virtual high‐throughput screening improved hit rates over traditional high‐throughput screening. The SENP 8 inhibitor candidates can be used to interrogate the NEDD ylation regulation mechanism.