Important Hydrogen Bond Networks in Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Design Revealed by Crystal Structures of Imidazoleisoindole Derivatives with IDO1

Indoleamine
2,3-dioxygenase 1 (IDO1), promoting immune escape of
tumors, is a therapeutic target for the cancer immunotherapy. A number
of IDO1 inhibitors have been identified, but only limited structural
biology studies of IDO1 inhibitors are available to provide insights
on the binding mechanism of IDO1. In this study, we present the structure
of IDO1 in complex with 24, a NLG919 analogue with potent
activity. The complex structure revealed the imidazole nitrogen atom
of 24 to coordinate with the heme iron, and the imidazoleisoindole
core situated in pocket A with the 1-cyclohexylethanol moiety extended
to pocket B to interact with the surrounding residues. Most interestingly, 24 formed an extensive hydrogen bond network with IDO1, which
is a distinct feature of IDO1/24 complex structure and
is not observed in the other IDO1 complex structures. Further structure–activity
relationship, UV spectra, and structural biology studies of several
analogues of 24 demonstrated that extensive hydrophobic
interactions and the unique hydrogen bonding network contribute to
the great potency of imidazoleisoindole derivatives. These results
are expected to facilitate the structure-based drug design of new
IDO inhibitors.