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

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Pages1354-1363
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number3
DOIs
Publication statusPublished - 1 Feb 2012

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Computer Simulation
Heme
Kynurenine
Immunosuppressive Agents
Tryptophan
Inhibitory Concentration 50
Tumors
Databases
Enzymes
Growth
Neoplasms
Therapeutics

Cite this

Smith, Jason R. ; Evans, Krystal J. ; Wright, Adam ; Willows, Robert D. ; Jamie, Joanne F. ; Griffith, Renate. / Novel indoleamine 2,3-dioxygenase-1 inhibitors from a multistep in silico screen. In: Bioorganic and Medicinal Chemistry. 2012 ; Vol. 20, No. 3. pp. 1354-1363.
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Novel indoleamine 2,3-dioxygenase-1 inhibitors from a multistep in silico screen. / Smith, Jason R.; Evans, Krystal J.; Wright, Adam; Willows, Robert D.; Jamie, Joanne F.; Griffith, Renate.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 3, 01.02.2012, p. 1354-1363.

Research output: Contribution to journalArticleResearchpeer-review

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