title: Discovery and structural analyses of S-adenosyl-L-homocysteine hydrolase inhibitors based on non-adenosine analogs.
abstract: Optimization of a new series of S-adenosyl-L-homocysteine hydrolase (AdoHcyase) inhibitors based on non-adenosine analogs led to very potent compounds 14n, 18a, and 18b with IC50 values of 13 ± 3, 5.0 ± 2.0, and 8.5 ± 3.1 nM, respectively. An X-ray crystal structure of AdoHcyase with NAD(+) and 18a showed a novel open form co-crystal structure. 18a in the co-crystals formed intramolecular eight membered ring hydrogen bond formations. A single crystal X-ray structure of 14n also showed an intramolecular eight-membered ring hydrogen bond interaction.
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. Electronic address: Nakao.Akira@mc.mt-pharma.co.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Nakao
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ueno
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Setsuta
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kashima
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Sunada
mesh_terms: D000241:Adenosine / Q000737:chemistry; D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007536:Isomerism; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009243:NAD / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D009243:NAD; D043383:Adenosylhomocysteinase; D000241:Adenosine
keywords: Homocysteine; Intramolecular eight-membered ring hydrogen bond interaction; S-Adenosyl-l-homocysteine hydrolase; X-ray crystal structure; cis-Amide