Design and screening strategies for alpha-glucosidase inhibitors based on enzymological information.
Alpha-glucosidase inhibitors are marketed as therapeutic drugs for diabetes that act through the inhibition of carbohydrate metabolism. Inhibitors of the alpha-glucosidases that are involved in the biosynthesis of N-linked oligosaccharide chains have been reported to have antitumor, antiviral, and apoptosis-inducing activities, and some have been used clinically. alpha-Glucosidase inhibitors have interesting biological activities, and their design, synthesis, and screening are being actively performed. In quite a few reports, however, alpha-glucosidases with different origins than the target alpha-glucosidases, have been used to evaluate inhibitory activities. There might be confusion regarding the naming of alpha-glucosidases. For example, the term alpha-glucosidase is sometimes used as a generic name for alpha-glucoside hydrolases. Moreover, IUBMB recommends the use of "alpha-glucosidase" (EC 3.2.1.20) for exo-alpha-1,4-glucosidases, which are further classified into four families based on amino acid sequence similarities. Accordingly, substrate specificity and susceptibility to inhibitors varies markedly among enzymes in the IUBMB alpha-glucosidases. The design and screening of inhibitors without consideration of these differences is not efficient. For the development of a practical inhibitor that is operational in cells, HTS using the target alpha-glucosidase and the computer-aided design of inhibitors based on enzymatic information concerning the same alpha-glucosidase are essential.
Hakamata
Wataru
W
Department of Biological Chemistry, College of Bioresource Sciences, Nihon University, Japan. hakamata.wataru@nihon-u.ac.jp
Kurihara
Masaaki
M
Okuda
Haruhiro
H
Nishio
Toshiyuki
T
Oku
Tadatake
T
D002240:Carbohydrate Sequence; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D065089:Glycoside Hydrolase Inhibitors; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000520:alpha-Glucosidases / Q000145:classification / Q000378:metabolism
D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D000520:alpha-Glucosidases