Unit:
Κατεύθυνση ΒιοχημείαLibrary of the School of Science
Supervisors info:
Αθανασία Σιαφάκα-Καπάδαη, Καθηγήτρια, Επιβλέπουσα
Original Title:
Δομικές μελέτες αναστολέων της φωσφορυλάσης του γλυκογόνου με κρυσταλλογραφία ακτίνων Χ
Summary:
The structure-based drug design approach exploits the knowledge of the three
dimensional structure of a macromolecular target with the aim to design
compounds of high affinity and increased specificity against a disease.
The current approach was applied on the glycogen phosphorylase enzyme a
validated molecular target for treatment of type 2 diabetes disease (T2D). T2D
or non insulin dependent diabetes accounts for 90-95% of the patients suffering
from diabetes worldwide and is closely related to other major diseases such as
ischemia, kidney failure and cardiovascular disease.
Previous kinetic studies of β-D-glucopyranozyl- guanine and aromatic-cytosine
derivatives were performed in the laboratory of Structural Biology and
Chemistry at the National Hellenic Research Foundation, for assessing their
inhibitory effect on glycogen phosphorylase enzymic action, showed that they
are potent inhibitors of the enzyme with inhibition in the range of μΜ and nM,
respectively.
In the frame of the present project, structural studies of glycogen
phosphorylase in complex with the individual derivatives were conducted. Native
enzyme crystals soaked with the inhibitors or co-crystals of the enzyme:ligand
complex were exposed to x-rays produced by synchrotron radiation and high
resolution data were collected. The results showed that the best inhibitor
among guanine derivatives examined, was bound at the catalytic site of the
enzyme (Ki 170 μΜ). In contrast, the rest of the guanine analogues bound at the
inhibitor site. Similar studies performed on the cytosine derivatives, revealed
that these compounds exhibit increased inhibitory effect, with the best
inhibitor being the anthracene cytosine (Ki 350 nΜ) and the three dimensional
structure showed that they bound at the catalytic site of the enzyme.
Keywords:
Type 2 diabetes, Glycogen metabolism, Glycogen phosphorylase, Crystallography, Structure based drug design
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