N-(4-Substituted-benzoyl)-N'-(β-d-glucopyranosyl)ureas as inhibitors of glycogen phosphorylase: Synthesis and evaluation by kinetic, crystallographic, and molecular modelling methods.
N-(4-Substituted-benzoyl)-N'-(β-d-glucopyranosyl) ureas (substituents: Me, Ph, Cl, OH, OMe, NO(2), NH(2), COOH, and COOMe) were synthesised by ZnCl(2) catalysed acylation of O-peracetylated β-d-glucopyranosyl urea as well as in reactions of O-peracetylated or O-unprotected glucopyranosylamines and acyl-isocyanates. O-deprotections were carried out by base or acid catalysed transesterifications where necessary. Kinetic studies revealed that most of these compounds were low micromolar inhibitors of rabbit muscle glycogen phosphorylase b (RMGPb). The best inhibitor was the 4-methylbenzoyl compound (K(i)=2.3μM). Crystallographic analyses of complexes of several of the compounds with RMGPb showed that the analogues exploited, together with water molecules, the available space at the β-pocket subsite and induced a more extended shift of the 280s loop compared to RMGPb in complex with the unsubstituted benzoyl urea. The results suggest the key role of the water molecules in ligand binding and structure-based ligand design. Molecular docking study of selected inhibitors was done to show the ability of the binding affinity prediction. The binding affinity of the highest scored docked poses was calculated and correlated with experimentally measured K(i) values. Results show that correlation is high with the R-squared (R(2)) coefficient over 0.9.
Department of Organic Chemistry, University of Debrecen, Debrecen, Hungary.
Veronika
V
Nagy
Nóra
N
Felföldi
Bálint
B
Kónya
Jean-Pierre
JP
Praly
Tibor
T
Docsa
Pál
P
Gergely
Evangelia D
ED
Chrysina
Costas
C
Tiraidis
Magda N
MN
Kosmopoulou
Kyra-Melinda
KM
Alexacou
Maria
M
Konstantakaki
Demetres D
DD
Leonidas
Spyros E
SE
Zographos
Nikos G
NG
Oikonomakos
Stanislav
S
Kozmon
Igor
I
Tvaroška
László
L
Somsák
D000818:Animals; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D024982:Glycogen Phosphorylase, Muscle Form / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D011817:Rabbits; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D014508:Urea; D024981:Glycogen Phosphorylase; D024982:Glycogen Phosphorylase, Muscle Form