ΠΜΣ με ειδίκευση ΣΥΝΘΕΤΙΚΗ ΦΑΡΜΑΚΕΥΤΙΚΗ ΧΗΜΕΙΑ
Library of the School of Science

2016-04-13

2016

Φαντέλ Άννα-Μαρία

Εμμανουήλ Μικρός Καθηγητής (Επιβλέπων), Ανδρέας Παπαπετρόπουλος Καθηγητής

Φαρμακολογικός Έλεγχος Ενώσεων Με Πιθανή Ανασταλτική Δράση Του Ενζύμου β-Συνθετάση Της Κυσταθειονίνης CBS Και Σχεδιασμός Θεωρητικών Υπολογιστικών Μοντέλων

Greek

Virtual and experimental screening of compound libraries for identifying inhibitors of cystathionine β-synthase

Cystathionineβ-synthase (CBS) isapyridoxal-5-phosphate (PLP) dependentenzyme.
CBS catalyzes the condensation of homocysteine and cysteine to give
cystathionine and hydrogen sulfide (H2S), a signaling molecule that belongs to
the gas transmitter family. Cystathionine β-synthase (CBS) among with
cystathionine γ-lyase (CSE) and 3-Mercaptopyruvate sulfurtrasferase (3-MST) are
responsible for hydrogen sulphide biogenesis in mammalian tissues. H2S is
increasingly recognized as an important biological and pharmacological
mediator. Deficiency in Η2S production is known to be involved in various
pathological disorders such as homocystinuria, an inborn error of cystathionine
metabolism resulting to arterial disease. In contrast, increased levels of
produced H2S have been associated with the development of colon cancer.
Consequently, CBS represents an attractive drug target.
The aim of this study was to identify compounds that selectively bind to
CBS enzyme and modulate its activity. The in-house library of natural products
and synthetic analogues of University of Athens comprising ~2K molecules of
exquisite structural originality and molecule of NCI library was evaluated. A
tandem screening approach based on the combination of virtual and experimental
methodologies was utilized. Virtual screening was based on two complementary
methods, namely 3D-molecular similarity and docking-scoring calculations by
utilizing ROCS and GLIDE software, respectively. Then, a consensus scheme was
used for combining results aiming at selecting the top-ranked molecules. The
most promising candidates were evaluated in vitro using recombinant CBS and a
colorimetric assay measuring the production of Hydrogen Sulfide. Screening
afforded a number of compounds with interesting modulating properties against
CBS and the IC50 values of the most potent inhibitors were calculated by
dose-response curves. Interestingly, the strongest effect was demonstrated by
derivatives of the pyrazolopyridine scaffold. Docking calculations were
subsequently undertaken to gain insight to the interactions of these compounds
with the CBS active site performed for providing further insight concerning.

Cystathionine beta synthase, Hydrogen sulfde, Virtual screening, PLP, In Vitro

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https://pergamos.lib.uoa.gr/uoa/dl/object/1320633