Unit:
Κατεύθυνση ΒιοχημείαLibrary of the School of Science
Author:
Παπακωνσταντίνου Μαρία
Supervisors info:
Αθανασία Σιαφάκα-Καπάδαη Kαθηγήτρια ΕΚΠΑ (επιβλέπουσα), Θωμάς Μαυρομούστακος Καθηγητής ΕΚΠΑ, Αθανάσιος Γκιμήσης Αναπλ. Καθηγητής ΕΚΠΑ
Original Title:
Κατευθυνόμενος-από τη δομή-σχεδιασμός νέων εν δυνάμει υπογλυκαιμικών φαρμάκων με βάση γνωστά βιοδραστικά μόρια ή θραύσματα
Translated title:
Structure-based design new potential hypoglycemic drugs based on known bioactive molecules or fragments
Summary:
Diabetes mellitus type 2 (or non-insulin dependent diabetes) affects 90-95 % of
patients suffering from the disease and is associated with serious diseases
such as ischemic stroke, renal failure, cardiovascular disease, and according
to recent studies wth cancer. Glycogen phosphorylase, a key enzyme in glycogen
metabolism that regulates blood sugar levels, is used as a molecular target for
the discovery and design of potential hypoglycemic drugs for the treatment of
diabetes mellitus type 2.
The method of structure-based drug design is applied on this enzyme to allow
the identification of compounds with high affinity and specificity for the
macromolecular target. In the frame of the present MSc thesis, the results from
structural studies of compounds that were previously evaluated for their
inhibitory potency against glycogen phosphorylase are reported. The complex
structures of glycogen phosphorylase in a complex with a) four organic
compounds glucose derivatives and b) five fragments derived from known
inhibitors’ scaffold have been determined at high resolution using X-rays from
synchrotron radiation sources. More specifically,the glucose derivatives
studied, were generated by introducing amino - acyl substituentsin the β-
anomeric position of glucose in order to examine the possibility of increasing
the binding affinity of compounds to the catalytic site. The results confirmed
the findings of the kinetic studies showing that those compoundspromotethe
inactive T state conformation and inhibit the enzyme’s action. In the case of
fragments, most of which are part of known inhibitorsof the enzyme,exhibited
weak affinity for the enzyme. However, there were found to bind at the new
allosteric site and the inhibitor site of the glycogen phoshorylase in
accordance with their lead compounds. Although the glucose derivatives is the
most obvious class of compounds for the design of antidiabetic agents, it
appears that the investigation of the role of fragments and their interactions
upon binding at the enzyme with X-ray crystallography sheds light to their
significance and might lead to useful observations for the “structural
affinity” some functional groups such as indole or naphthyl groups exhibit for
the distinct inhibitor binding sites of the enzyme.
Keywords:
Type 2 diabetes, Glycogen metabolism, Glycogen phosphorylase, Structure-based drug design, X-ray crystallography
Number of index pages:
1-10
