Coumarin and chromen-4-one analogues as tautomerase inhibitors of macrophage migration inhibitory factor: discovery and X-ray crystallography.
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine released from T-cells and macrophages. Although a detailed understanding of the biological functions of MIF has not yet been clarified, it is known that MIF catalyzes the tautomerization of a nonphysiological molecule, D-dopachrome. Using a structure-based computer-assisted search of two databases of commercially available compounds, we have found 14 novel tautomerase inhibitors of MIF whose K(i) values are in the range of 0.038-7.4 microM. We also have determined the crystal structure of MIF complexed with the hit compound 1. It showed that the hit compound is located in the active site of MIF containing the N-terminal proline which plays an important role in the tautomerase reaction and forms several hydrogen bonds and undergoes hydrophobic interactions. A crystallographic study also revealed that there is a hydrophobic surface which consists of Pro-33, Tyr-36, Trp-108, and Phe-113 at the rim of the active site of MIF, and molecular modeling studies indicated that several more potent hit compounds have the aromatic rings which can interact with this hydrophobic surface. To our knowledge, our compounds are the most potent tautomerase inhibitors of MIF. One of these small, drug-like molecules has been cocrystallized with MIF and binds to the active site for tautomerase activity. Molecular modeling also suggests that the other hit compounds can bind in a similar fashion.
Orita
M
M
Yamanouchi Pharmaceutical Company Ltd., 21 Miyukigaoka, Tsukuba Science City 305-8585, Japan. orita@yamanouchi.co.jp
Yamamoto
S
S
Katayama
N
N
Aoki
M
M
Takayama
K
K
Yamagiwa
Y
Y
Seki
N
N
Suzuki
H
H
Kurihara
H
H
Sakashita
H
H
Takeuchi
M
M
Fujita
S
S
Yamada
T
T
Tanaka
A
A
D001665:Binding Sites; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D002867:Chromones; D003374:Coumarins; D004791:Enzyme Inhibitors; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase