Structure based development of phenylimidazole-derived inhibitors of indoleamine 2,3-dioxygenase.
Indoleamine 2,3-dioxygenase (IDO) is emerging as an important new therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. With the goal of developing more potent IDO inhibitors, a systematic study of 4-phenylimidazole (4-PI) derivatives was undertaken. Computational docking experiments guided design and synthesis efforts with analogues of 4-PI. In particular, three interactions of 4-PI analogues with IDO were studied: the active site entrance, the interior of the active site, and the heme iron binding. The three most potent inhibitors (1, 17, and 18) appear to exploit interactions with C129 and S167 in the interior of the active site. All three inhibitors are approximately 10-fold more potent than 4-PI. The study represents the first example of enzyme inhibitor development with the recently reported crystal structure of IDO and offers important lessons in the search for more potent inhibitors.
Kumar
Sanjeev
S
Department of Chemistry, Bryn Mawr College, Bryn Mawr, Pennsylvania 19010, USA.
Jaller
Daniel
D
Patel
Bhumika
B
LaLonde
Judith M
JM
DuHadaway
James B
JB
Malachowski
William P
WP
Prendergast
George C
GC
Muller
Alexander J
AJ
D000595:Amino Acid Sequence; D001665:Binding Sites / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006418:Heme / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D007501:Iron / Q000378:metabolism; D008958:Models, Molecular; D011789:Quantum Theory; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007093:Imidazoles; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D006418:Heme; D007501:Iron