Εικονική και πειραματική αξιολόγηση αναστολέων φωσφορυλάσης του γλυκογόνου

Postgraduate Thesis uoadl:1317067 634 Read counter

Unit:
Κατεύθυνση Παραγωγή Φαρμακευτικών Ενώσεων (Σύνθεση)
Library of the School of Science
Deposit date:
2012-02-01
Year:
2012
Author:
Μαυροκέφαλος Νικόλαος
Supervisors info:
Μικρός Ε., Καθηγητής ΕΚΠΑ
Original Title:
Εικονική και πειραματική αξιολόγηση αναστολέων φωσφορυλάσης του γλυκογόνου
Languages:
Greek
Summary:
In this study computational methods and biological experiments were applied for
the evaluation of, the Diversity Set of NCI and the compounds that have been
synthesized and isolated by the Pharmaceutical University of Athens, aiming at
the discovery of new inhibitors for protein glycogen phosphorylase.
The study is divided in three steps: a) Protein calibration with a known
activity set (decoy set), b) Virtual screening of the unknown activity set and
c) Determination of the IC50 of the ligands that best ranked of the unknown
activity set.
For the protein calibration the decoy set was virtually screened with
Schrodinger Suite and evaluated with the enrichment factor (EF).
The evaluation of water molecules of the catalytic site revealed 29 of those to
be structural and were kept as part of the rigid protein. Optimization of the
parameters controlling the atomic van der waals radius of the complex (ligand
and protein) was carried out. The results and parameters that demonstrated best
prediction in the decoy set, were used to predict the activity of the unknown
set and the best candidates were evaluated experimentally.
From the compounds that turned up to have satisfactory theoretical binding
affinity, 18 were evaluated with enzymatic kinetic and 10 of them showed a
degree of inhibition for the protein phosphorylase. Two of them, resveratrol
glucoside and tachioside turned out with the best inhibition of the biological
evaluated molecules and their IC50 was obtained. These two molecules could be
lead compounds for future synthetic inhibitors for the protein glycogen
phosphorylase.
Keywords:
Phosphorylase, Virtual Screening, Water Molecules, Diabetes, Glycogene
Index:
No
Number of index pages:
0
Contains images:
Yes
Number of references:
37
Number of pages:
vi, 121
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