Naturally occurring pentacyclic triterpenes as inhibitors of glycogen phosphorylase: synthesis, structure-activity relationships, and X-ray crystallographic studies.
Twenty-five naturally occurring pentacyclic triterpenes, 15 of which were synthesized in this study, were biologically evaluated as inhibitors of rabbit muscle glycogen phosphorylase a (GPa). From SAR studies, the presence of a sugar moiety in triterpene saponins resulted in a markedly decreased activity ( 7, 18- 20) or no activity ( 21, 22). These saponins, however, might find their value as potential natural prodrugs which are much more water-soluble than their corresponding aglycones. To elucidate the mechanism of GP inhibition, we have determined the crystal structures of the GPb-asiatic acid and GPb-maslinic acid complexes. The X-ray analysis indicates that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Pentacyclic triterpenes represent a promising class of multiple-target antidiabetic agents that exert hypoglycemic effects, at least in part, through GP inhibition.
Wen
Xiaoan
X
Center for Drug Discovery, College of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
Sun
Hongbin
H
Liu
Jun
J
Cheng
Keguang
K
Zhang
Pu
P
Zhang
Liying
L
Hao
Jia
J
Zhang
Luyong
L
Ni
Peizhou
P
Zographos
Spyros E
SE
Leonidas
Demetres D
DD
Alexacou
Kyra-Melinda
KM
Gimisis
Thanasis
T
Hayes
Joseph M
JM
Oikonomakos
Nikos G
NG
D000249:Adenosine Monophosphate / Q000737:chemistry; D000495:Allosteric Site; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D009132:Muscles / Q000201:enzymology; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D053978:Pentacyclic Triterpenes; D011485:Protein Binding; D011487:Protein Conformation; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry
D007004:Hypoglycemic Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C525519:augustic acid; D000249:Adenosine Monophosphate; D009828:Oleanolic Acid; C017032:asiatic acid; C113861:corosolic acid; C412811:maslinic acid; D024981:Glycogen Phosphorylase