Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Indoleamine 2,3-dioxygenase 1 (IDO1) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. Starting from the scaffold of our previously discovered IDO1 inhibitor 4-phenyl-1,2,3-triazole, we used computational structure-based methods to design more potent ligands. This approach yielded highly efficient low molecular weight inhibitors, the most active being of nanomolar potency both in an enzymatic and in a cellular assay, while showing no cellular toxicity and a high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). A quantitative structure-activity relationship based on the electrostatic ligand-protein interactions in the docked binding modes and on the quantum chemically derived charges of the triazole ring demonstrated a good explanatory power for the observed activities.

Original publication

DOI

10.1021/jm300260v

Type

Journal article

Journal

J Med Chem

Publication Date

14/06/2012

Volume

55

Pages

5270 - 5290

Keywords

Animals, Catalytic Domain, Cell Line, Drug Design, Enzyme Assays, Humans, Hydrogen Bonding, Hydrophobic and Hydrophilic Interactions, Imidazoles, Indoleamine-Pyrrole 2,3,-Dioxygenase, Ligands, Mice, Models, Molecular, Protein Binding, Protein Conformation, Quantitative Structure-Activity Relationship, Quantum Theory, Static Electricity, Triazoles, Tryptophan Oxygenase