Structural requirements of the competitive binding site of recombinant human indoleamine 2,3-dioxygenase

Michael D. Southan*, Roger J W Truscott, Joanne F. Jamie, Luciana Pelosi, Mark J. Walker, Hiroyasu Maeda, Yoshiki Iwamoto, Shigenobu Toné

*Corresponding author for this work

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

The structural requirements for substrate/inhibitor binding to the active site of recombinant human IDO are reported in this paper. Tryptophan analogues with substituents at the 5 or 6 positions were found to bind to the tryptophan binding site of IDO and serve as either substrates or inhibitors. Analogues that were more effective as substrates than inhibitors include 5-methyl-D,L-tryptophan 18, 5-methoxy-D,L-tryptophan 19, 5-hydroxy-L-tryptophan 21 and 6-methyl-D,L-tryptophan 24. Interestingly, 5-methyl-D,L-tryptophan appeared to be a better substrate than L-tryptophan. Compounds which were more active as inhibitors than substrates include 5-bromo-D,L-tryptophan 22 and 6-fluoro-D,L-tryptophan 25. 5-Fluoro-D,L-tryptophan 23 was slightly more active as a substrate. The most effective competitive inhibitor of recombinant human IDO was 6-nitro-L-tryptophan 26 which inhibited enzyme activity 52% at 1 mM concentrations (Ki = 180 μM) and was not active as a substrate. The optical isomer, 6-nitro-D-tryptophan 27 did not inhibit IDO activity indicating that binding to the active site is stereoselective. An analogue with a large substituent at the 5 position, 5-benzyloxy-D,L-tryptophan 20, was excluded from the active site. Compounds with substituents at other positions around the indole ring or the amino acid portion of tryptophan generally have low activity as substrates or inhibitors although the benzofuran analogue 5 gave moderate (43%) inhibition.

Original languageEnglish
Pages (from-to)343-352
Number of pages10
JournalMedicinal Chemistry Research
Volume6
Issue number5
Publication statusPublished - 1996
Externally publishedYes

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    Southan, M. D., Truscott, R. J. W., Jamie, J. F., Pelosi, L., Walker, M. J., Maeda, H., ... Toné, S. (1996). Structural requirements of the competitive binding site of recombinant human indoleamine 2,3-dioxygenase. Medicinal Chemistry Research, 6(5), 343-352.