Κατεύθυνση Οργανική Χημεία
Library of the School of Science

2014-05-02

2014

Ανδρεαδέλης Ιωάννης

Θωμάς Μαυρομούστακος Καθηγητής ΕΚΠΑ (Επιβλέπων), Γεώργιος Κόκοτος Καθηγητής ΕΚΠΑ, Γεώργιος Λιαπάκης Αναπλ. Καθηγητής Πανεπιστήμιο Κρήτης

Ορθολογικός σχεδιασμός καινοτόμων μοριών με πιθανή αντικαταθλιπτική και εκλεκτική δράση που αλληλεπιδρούν με το εξωκυττάριο τμήμα του CRF1

Greek

Rational design of novel selective inhibitors with possible antidepressant activity that interact with the extracellular domain of CRF1

In this thesis rational design was applied to reveal novel molecules with
possible antidepressant activity that act as selective orthosteric antagonists
of type 1 receptor (CRF1R) for the corticotropin releasing factor (CRF). Based
on a tripeptide part consisting of the aminoacids Leu37, Met38 and Ile41 of the
natural agonist,CRF, novel compounds have been designed utilizing
peptidomimetism and bioisosterism. Consequently, pharmacophores were generated
from these compounds in order to scan an extensive number of commercially
available molecules. This approach, resulted to an isolation of few compounds
that exhibited high docking affinity, selectivity and acceptable
pharmacological properties. Using molecular dynamics, we were able to extract
useful information about the nature of the bonds and the binding energy of the
complex receptor-molecule. The two diastereoisomers of tripeptide Leu-Met- Ile
with the absolute configurations SSS and RSS showed the best docking score.
Initial in vitro biological experiments, showed that these are promising
antagonistic compounds. More biological experiments are under progress to test
their selectivity for CRF1R versus the type 2 CRF receptor (CRF2R). Another
commercial organic compound, named according to IUPAC
1-[[2-[(2-methyl-1H-indol-3-yl)sulfanyl]acetyl] amino]trifluromethoxy)phenyl]
urea, was purchased and it will be subjected soon to biological tests.

Antidepressants, CRF1R, Molecular dynamics , Molecular docking, Pharmacophore

Yes

1-12

Yes

55

156

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https://pergamos.lib.uoa.gr/uoa/dl/object/1319295