Identification of the New Covalent Allosteric Binding Site of Fructose-1,6-bisphosphatase with Disulfiram Derivatives toward Glucose Reduction
- 7 May 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (11), 6238-6247
- https://doi.org/10.1021/acs.jmedchem.0c00699
Abstract
Fructose 1,6-bisphosphatase (FBPase) has attracted substantial interest as a target associated with cancer and type 2 diabetes. Herein, we found that disulfiram and its derivatives can potently inhibit FBPase by covalently binding to a new C128 allosteric site distinct from the original C128 site in APO FBPase. Further identification of allosteric inhibition mechanism reveal that the covalent binding of a fragment of 214 will result in the movement of C128 and the dissociation of helix H4 (123-128), which in turn allows S123 to more easily form new hydrogen-bonds with K71 and D74 in helix H3 (69-72), thereby inhibiting FBPase activity. Notably, both disulfiram and 212 might moderately reduce blood glucose output in vivo. Therefore, our current findings not only identify a new covalent allosteric site of FBPase, but also establish a structural foundation and provide a promising way for the design of covalent allosteric drugs for glucose reduction.Keywords
Funding Information
- State Administration of Foreign Experts Affairs (B17019)
- Ministry of Education of the People's Republic of China (2018YBZZ019, B17019, IRT0953)
- Central China Normal University (CCNU16A02041, CCNU18TS010, CCNU19TS011)
- National Natural Science Foundation of China (21472061, 21572077, 21873035, 21877046)
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