Macrophage migration inhibitory factor and the discovery of tautomerase inhibitors.
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine released from T-cells and macrophages, and is a key molecule in inflammation. Although a detailed understanding of the biological functions of MIF has not yet been found, it is known that MIF catalyzes the tautomerization of phenylpyruvate and a non-physiological molecule, D-dopachrome. A potent tautomerase inhibitor would be expected, as a validation tool, to shed light on role of MIF activity and the relationship between its biological and enzymatic activity. Such tautomerase inhibitors would be useful in the treatment of MIF-related diseases, such as sepsis, acute respiratory distress syndrome (ARDS), asthma, atopic dermatitis, rheumatoid arthritis (RA), nephropathy and tumors. In this review, we have focused on (1) the biological and enzymatic activities of MIF, (2) the discovery of novel, drug-like tautomerase inhibitors of MIF using a structure-based computer-assisted search, and (3) a crystallographic and molecular modeling study of the MIF-tautomerase inhibitor complexes (A review with 133 references).
Orita
Masaya
M
Yamanouchi Pharmaceutical Co. Ltd., Tsukuba Science City 305-8585, Japan. orita@yamanouchi.co.jp
Yamamoto
Satoshi
S
Katayama
Naoko
N
Fujita
Shigeo
S
D001665:Binding Sites; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase