Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 7, Issue 9, Pages 868-872Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.6b00241
Keywords
Delta-S desaturase; T-3364366; slow-binding inhibition; mechanism of action (MOA)
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Delta-5 desaturase (D5D) catalyzes the conversion from dihomo-gamma linoleic acid (DGLA) to arachidonic acid (AA). DGLA and AA are common precursors of anti- and pro-inflammatory eicosanoids, respectively, making D5D an attractive drug target for inflammatory-related diseases. Despite several reports on D5D inhibitors, their biochemical mechanisms of action (MOAs) remain poorly understood, primarily due to the difficulty in performing quantitative enzymatic analysis. Herein, we report a radio-ligand binding assay to overcome this challenge and characterized T-3364366, a thienopyrimidinone D5D inhibitor, by use of the assay. T-3364366 is a reversible, slow-binding inhibitor with a dissociation half-life in excess of 2.0 h. The long residence time was confirmed in cellular washout assays. Domain swapping experiments between D5D and D6D support [H-3]T-3364366 binding to the desaturase domain of D5D. The present study is the first to demonstrate biochemical MOA of desaturase inhibitors, providing important insight into drug discovery of desaturase enzymes.
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