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.
Center for Drug Discovery, College of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
Xiaoan
X
Wen
Hongbin
H
Sun
Jun
J
Liu
Keguang
K
Cheng
Pu
P
Zhang
Liying
L
Zhang
Jia
J
Hao
Luyong
L
Zhang
Peizhou
P
Ni
Spyros E
SE
Zographos
Demetres D
DD
Leonidas
Kyra-Melinda
KM
Alexacou
Thanasis
T
Gimisis
Joseph M
JM
Hayes
Nikos G
NG
Oikonomakos
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