Discovery of covalent inhibitors for MIF tautomerase via cocrystal structures with phantom hits from virtual screening.
Biochemical and X-ray crystallographic studies confirmed that hydroxyquinoline derivatives identified by virtual screening were actually covalent inhibitors of the MIF tautomerase. Adducts were formed by N-alkylation of the Pro-1 at the catalytic site with a loss of an amino group of the inhibitor.
McLean
Larry R
LR
Discovery Research, sanofi-aventis, Bridgewater, NJ 08807, USA. Larry.Mclean@sanofi-aventis.com
Zhang
Ying
Y
Li
Hua
H
Li
Ziyu
Z
Lukasczyk
Ulrike
U
Choi
Yong-Mi
YM
Han
Zuoning
Z
Prisco
Joy
J
Fordham
Jeremy
J
Tsay
Joseph T
JT
Reiling
Stephan
S
Vaz
Roy J
RJ
Li
Yi
Y
D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006912:Hydroxyquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D006912:Hydroxyquinolines; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases