Kinetic and structural studies of glycogen phorphorylase for the development of potential anti diabetic agents

Postgraduate Thesis uoadl:1318138 442 Read counter

Unit:
Κατεύθυνση Βιοχημεία
Library of the School of Science
Deposit date:
2015-07-29
Year:
2015
Author:
Σωτηροπούλου Αναστασία
Supervisors info:
Αθανασία Σιαφάκα-Καπάδαη -- Καθηγήτρια ΕΚΠΑ
Original Title:
Κινητικές και κρυσταλλογραφικές μελέτες του ενζύμου φωσφορυλάση του γλυκογόνου για την ανάπτυξη δυνάμει αντιδιαβητικών φαρμάκων
Languages:
Greek
Translated title:
Kinetic and structural studies of glycogen phorphorylase for the development of potential anti diabetic agents
Summary:
The structure-based drug design approach has been applied on glycogen
phosphorylase a key enzyme in glycogen metabolism that is exploited as a
therapeutic target for the treatment of type 2 diabetes. In the frame of the
present study, kinetic studies of glucopyranose based 5-halogen-1,2,3-
triazoles and amides were perfomed along with structural studies of
glucopyranosyl-spiroisoxazolines in complex with RMGPb using X-ray
crystallography. In addition, β-D-xylopyranose derivatives were examined with
the aim to identify the structural determinants that contribute to the ligand
binding affinity for the catalytic site of the enzyme, beyond the specificity
induced by the glucose moiety.Native crystals of RMGPb were soaked in various
ligand solutions of known concentration. The results showed that introduction
of of 5-alkinyl and 5-phenyl groups at 1,2,3-triazoles pointing towards the α-
subsite were not favourable for ligand binding at the active site of the
enzyme. The results though were exciting for the β-D-xylose derivatives, which
for the first time, showed thatthey bind at the catalytic site of RMGPb. This
provides new insights for the role of sugar as the leading or driving component
for ligand binding as compared to the aromatic substituents like naphthoyl
groups.
Keywords:
Type 2 diabetes, Glycogen phorphorylase, Structure-based drug design, Χylose derivatives, X-ray protein crystallography
Index:
Yes
Number of index pages:
1-11
Contains images:
Yes
Number of references:
60
Number of pages:
164
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