Identifying De‐NEDDylation Inhibitors: Virtual High‐Throughput Screens Targeting SENP8

SENP8 inhibitors, to investigate de‐NEDDylation, were identified via virtual high‐throughput screening. Experimental validation of activity for a subset of candidates yielded 4 actives in 10 candidates in the initial screen and 1 active in 5 candidates in the second screen. Analysis of the tested candidates and compounds in the training data yielded a potential new scaffold for further investigation beyond the five actives identified.

Abstract

Protein modification can have far‐reaching effects. NEDDylation, a protein modification process with the protein NEDD8, stabilizes and modifies how the targeted protein interacts with other proteins. Its role in system regulation make it a prime therapeutic target, and virtual high throughput screening has already identified new NEDD8 inhibitors. SENP8 matures the NEDD8 proenzyme into the active form and regulates NEDDylation by removing NEDD8 from over‐NEDDylated proteins. In this work, SENP8 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 SENP8 inhibitor candidates can be used to interrogate the NEDDylation regulation mechanism.

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