Novel indoleamine 2,3-dioxygenase-1 inhibitors from a multistep in silico screen

Jason R. Smith, Krystal J. Evans, Adam Wright, Robert D. Willows, Joanne F. Jamie*, Renate Griffith

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

Indoleamine 2,3-dioxygenase-1 (IDO-1) is a heme containing enzyme that catalyses the initial step in the major pathway of l-tryptophan catabolism; the kynurenine pathway. A large body of evidence has been accumulating for its immunosuppressive and tumoural escape roles and its applicability as a therapeutic target. Of particular interest is the possibility that IDO-1 inhibition may arrest, and sometimes revert, tumour growth. There exists a continuing need for the development of new and specific inhibitors for IDO-1, and we have created three pharmacophores designed to aid in this search. Initial database hits were further screened using Kier flexibility and a 'What-If' docking technique, designed to overcome the inherent limitations of today's forcefields with regards to heme chemistry. Eighteen compounds were tested in vitro, yielding four novel inhibitors with low micromolar IC50 values, comparable with current inhibitors.

Original languageEnglish
Pages (from-to)1354-1363
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number3
DOIs
Publication statusPublished - 1 Feb 2012

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