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US 12,565,673 B2Granted
Methods for the design of nonallosteric sirtuin activating compounds
AssigneeChakrabarti Advanced Technology LLC
InventorsRaj Chakrabarti, Xiangying Guan, Alok Upadhyay
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Abstract
The present invention provides workflows for the discovery of nonallosteric sirtuin activation compounds. Workflows enable drug discovery of novel sirtuin activating compounds with prescribed effects on the binding in pockets near the active site interacting with flexible protein degrees of freedom around the active site. Novel kinetic models are used to confirm hit compounds and to improve their properties.
Claims18
A method for identifying a test compound for a mechanism-based sirtuin activating compound (MB-STAC), the method comprising:
- establishing a library of compounds on the basis of the compounds exhibiting computational docking with at least one sirtuin complex selected from the group consisting of sirtuin+peptide substrate complex, sirtuin+peptide substrate+NAD+ complex, sirtuin+alkylimidate intermediate+NAM complex, sirtuin+alkylimidate complex, and sirtuin+O-AADPR complex;
- and
- a) incubating a test compound from the library of compounds with a sirtuin enzyme (E), NAD+, NAM, and a concentration of an acylated substrate peptide in an assay for deacylation activity;
- b) measuring non-steady state (vnon-ss) rate of sirtuin enzyme-catalyzed deacylation;
- and
- c) identifying the test compound as a hit compound when the test compound induces sirtuin enzyme activation at an [E]0/[NAD+]0 ratio greater than 0.25 and less than 1.
3 more elements
Dependencies are inferred from the claim text.