Rational design, synthesis and in vitro evaluation of M1 aminopeptidases' inhibitors

Postgraduate Thesis uoadl:1320278 522 Read counter

Unit:
Κατεύθυνση Οργανική Χημεία
Library of the School of Science
Deposit date:
2016-02-24
Year:
2016
Author:
Κακού Μαγδαληνή
Supervisors info:
Γεωργιάδης Δημήτρης, Επίκ. Καθηγητής (Επιβλέπων), Βουρλούμης Διονύσης, Ερευνητής Α΄, Ευστράτιος Στρατίκος, Ερευνητής Α΄
Original Title:
Σχεδιασμός, σύνθεση και βιοχημική αξιολόγηση Μ1 αμινοπεπτιδασών
Languages:
Greek
Translated title:
Rational design, synthesis and in vitro evaluation of M1 aminopeptidases' inhibitors
Summary:
In this current study is carried out rational design and synthesis of
inhibitors for a specific class of metalloproteases enzymes, Endoplasmic
Reticulum (ER) aminopeptidases. The enzymes ERAP1, ERAP2 and IRAP, are
classified in this enzyme family and interfer in complex cellular signal
transduction pathways, such as antigenic peptide generation. Analyzing the
structure of the particular enzymes through crystallographic data, was executed
an effort to rationally design a number of potent inhibitors, using
computational docking calculations. The design of the inhibitors involves the
use of two characteristic groups (ZBGs), capable of bidentate binding to the
catalytic ion Ζn(II), the 3-hydroxy-2-pyridinone (A) and
3-hydroxy-2-pyridinethione (B). In these groups, appropriate substituents R1΄
and R2΄ were added, after their selection from a pool of amino acids and
amines, which were predicted to interact with specificity pockets of the
enzymes. These interactions are a prerequisite for the development of an active
and selective inhibitor. The computationally designed derivatives were
synthesized through consecutive steps and then evaluated in vitro for the three
enzymes.
These compounds were also studied biochemically and crystallographically for a
specific matrixin (MMP-12), due to common structural similarity with the
aminopeptidases.
Keywords:
ZBG, Inhibitors, Aminopeptidases, Inhibition potency, Specificity pockets
Index:
Yes
Number of index pages:
V-XVII, 92
Contains images:
Yes
Number of references:
157
Number of pages:
XVII, 143
File:
File access is restricted.

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