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.
| Language | English |
|---|---|
| Pages | 1354-1363 |
| Number of pages | 10 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 20 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 1 Feb 2012 |
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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 journal › Article › Research › peer-review
TY - JOUR
T1 - Novel indoleamine 2,3-dioxygenase-1 inhibitors from a multistep in silico screen
AU - Smith, Jason R.
AU - Evans, Krystal J.
AU - Wright, Adam
AU - Willows, Robert D.
AU - Jamie, Joanne F.
AU - Griffith, Renate
PY - 2012/2/1
Y1 - 2012/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84856224864&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2011.10.068
DO - 10.1016/j.bmc.2011.10.068
M3 - Article
VL - 20
SP - 1354
EP - 1363
JO - Bioorganic and Medicinal Chemistry
T2 - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 3
ER -