Novel concept of enzyme selective nicotinamide adenine dinucleotide (NAD)-modified inhibitors based on enzyme taxonomy from the diphosphate conformation of NAD

Mikio Fujii; Yasuyuki Kitagawa; Shui Iida; Keisuke Kato; Machiko Ono

doi:10.1016/j.bmcl.2015.10.005

Novel concept of enzyme selective nicotinamide adenine dinucleotide (NAD)-modified inhibitors based on enzyme taxonomy from the diphosphate conformation of NAD

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5133-6. doi: 10.1016/j.bmcl.2015.10.005. Epub 2015 Oct 9.

Authors

Mikio Fujii¹, Yasuyuki Kitagawa², Shui Iida³, Keisuke Kato³, Machiko Ono⁴

Affiliations

¹ School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan; Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan. Electronic address: mfujii@iuhw.ac.jp.
² School of Pharmacy, Yokohama College of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, Kanagawa 245-0066, Japan.
³ Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
⁴ School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan.

PMID: 26463132
DOI: 10.1016/j.bmcl.2015.10.005

Abstract

The dihedral angle θ of the diphosphate part of NAD(P) were investigated to distinguish the differences in the binding-conformation of NAD(P) to enzymes and to create an enzyme taxonomy. Furthermore, new inhibitors with fixed dihedral angles showed that enzymes could recognize the differences in the dihedral angle θ. We suggest the taxonomy and the dihedral angle θ are important values for chemists to consider when designing inhibitors and drugs that target enzymes.

Keywords: Conformation; Diphosphate; Enzyme selective inhibitor; Enzyme taxonomy; NAD(P).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chickens
Enzyme Inhibitors / chemistry*
Kinetics
Molecular Conformation
NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases / antagonists & inhibitors
NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases / chemistry*
NAD / analogs & derivatives*
NAD / chemistry*
Oxidoreductases / antagonists & inhibitors
Oxidoreductases / chemistry*
Oxidoreductases / classification
Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
Phosphotransferases (Alcohol Group Acceptor) / chemistry
Saccharomyces cerevisiae
Thiazoles / chemistry*

Substances

Enzyme Inhibitors
Thiazoles
NAD
Oxidoreductases
NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases
Phosphotransferases (Alcohol Group Acceptor)
NAD kinase