Unit:
Τομέας Ι [Θεωρητική Χημεία – Φυσικοχημεία – Ανόργανη Ανάλυση – Ενόργανη Ανάλυση – Οργανολογία – Χημική Μηχανική (Εφαρμ. Φυσικοχημεία)]Library of the School of Science
Author:
Σταυρινουδάκης Νικόλαος
Supervisors info:
Κόκοτος Γεώργιος Καθηγητής ΕΚΠΑ (επιβλέπων), Μαυρομούστακος Θωμάς Αναπλ. Καθηγητής ΕΚΠΑ, Μαγκριώτη Βικτώρια Λέκτορας ΕΚΠΑ
Original Title:
Πειράματα προσομοίωσης μοριακής πρόσδεσης πιθανών ισχυρών και εκλεκτικών αναστολέων της λιπάσης της μονοακυλογλυκερόλης
Summary:
2-Arachidonoylglycerol (2-AG) possesses a wide range of pharmacological
properties. These include the modulation of neurotransmitter release, control
of neuro-inflammation and regulation of cancer cell growth to stress-induced
analgesia. The enzyme monoacylglycerol lipase (MAGL) plays an important role in
its metabolism by in vivo hydrolyzing it. To restore its pharmacological
properties, MAGL inhibition is considered a putative therapeutic target.
First, we have applied in silico docking experiments of compounds with known
biological activity using existing software available in our laboratory in
order to validate the reported results. One significant problem we faced
exploring the literature data is that the inhibition of MAGL enzyme has been
determined by various biological assays which in some cases lead to
controversial results. To overcome this difficulty, we have applied and
compared docking results at the molecules subjected to identical biological
assays. Another problem encountered in the application of docking studies is
the presence of only two x-ray crystallographic results in which MAGL is
co-crystallized with an inhibitor. Such a short number of crystallographic data
makes difficult the decision of the exact mode of action for novel compounds as
they are found to approach in different ways the active or allosteric sites.
Except that, there is a difference between the open and the close form of the
tunnel containing the catalytic triad, so we had to test the results in both
forms of the enzyme.
After we have validated the data with known experimental biological values, we
applied molecular docking using a data base of novel compounds that have not
been evaluated biologically. Those compounds that showed the highest score were
also docked at the enzyme FAAH to test their selectivity between the two
enzymes. The pyrrolydinone analogues that were initially synthesized as renin
inhibitors showed the highest potency towards MAGL and adequate selectivity to
FAAH, indicating that they constitute a promising class of molecules to further
explore.
Keywords:
Endocannabinoid system, Pyrrolidinone derivatives, Molecular docking, Monoacylglycerol lipase, Fatty acid amide hydrolase
Number of index pages:
1-6
Number of references:
114
