Unit:
Τομέας ΙΙ [Οργανική Χημεία – Οργανική Χημική Τεχνολογία – Χημεία Τροφίμων]Library of the School of Science
Dissertation committee:
Γεώργιος Κόκοτος Καθηγητής ΕΚΠΑ (Επιβλέπων), Θωμάς Μαυρομούστακος Καθηγητής, Μάνθος Παπαδόπουλος Ερευνητής Α΄
Original Title:
Σχεδιασμός, σύνθεση και μελέτη αναστολέων της εκκριτικής φωσφολίπασης Α2 με πιθανή δράση κατά της αθηροσκλήρωσης
Translated title:
Design, Synthesis and Evaluation of New Inhibitors of Secreted Phospholipase A2 as Potential Agents Against Atherosclerosis.
Summary:
Secreted phospholipase A2 (sPLA2) is a family of enzymes that catalyze the
hydrolysis of membrane phospholipids at the sn-2 position. The products of this
reaction are unsaturated fatty acids, which amplify the production of
pre-inflammatory mediators. Group IIA sPLA2 has long been an important target
for medicinal chemists as it is highly expressed in synovial cells and in
atherosclerosis.
Kokotos group has developed novel 2-oxoamides inhibitors against various PLA2s.
Recently, a 2-oxoamide derivative based on (S)-leucine GK126 has shown potent
inhibitory activity against GIIA sPLA2. Herein, the design of new potent
inhibitors using GK126 as lead is described. Molecular docking simulations of
the new compounds performed using the docking program GOLD. The derivatives
presenting the most promising docking results were synthesized and their
inhibitory activity was evaluated by in vitro studies. The 2-oxoamide
derivative of (S)-valine GK241 showed a potent and selective inhibitory
activity. Thus, molecular dynamics simulations using AMBER were also performed
to further study its binding mode.
In addition, new coumarin and quinolinone derivatives were designed starting
from the structure of known indole inhibitors of GIIA sPLA2. Molecular docking
simulations of these derivatives in GOLD showed that some of them could bind
effectively on the active side of the enzyme and they represent new synthetic
targets.
Keywords:
Inhibitors, Secreted phospholipase A2, Docking, Dynamics simulations, 2-oxoamides
Number of index pages:
13-16
Number of references:
338
