Molekulsko uklapanje potencijalnih inhibitora na protein ABCG2

master's thesis

• Title (english): Docking study of interactions between the ABCG2 protein and potential inhibitors
• Author: Katarina Radman
• Mentor: Branimir Bertoša (mentor)
• Committee member: Branimir Bertoša (predsjednik povjerenstva)
• Committee member: Ivana Ivančić Baće (član povjerenstva)
• Committee member: Martina Šeruga Musić (član povjerenstva)
• Committee member: Biljana Balen (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2021-07-08, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology

Abstract

Protein ABCG2 je transmembranski protein koji djeluje kao pumpa za izbacivanje raznih endogenih
supstrata. Prekomjerna ekspresija proteina ABCG2 u stanicama karcinoma jedan je od glavnih uzroka
otpornosti stanica karcinoma na mnoge lijekove. Recentna istraživanja pokazala su potencijal
adamantil-supstituiranih diaza-krunastih etera (DAC) kao inhibitora proteina ABCG2. U sklopu ovog
diplomskog rada računalno je istraženo vezanje različitih DAC na protein ABCG2 te je njihovo vezanje
uspoređeno s vezanjem literaturno poznatih inhibitora i supstrata proteina ABCG2. Vezanje DAC te
poznatih inhibitora i supstrata proteina ABCG2 provedeno je metodom molekulskog uklapanja.
Napravljena su dva računa molekulskog uklapanja za svaki ligand. Prvi račun obuhvaćao je cijeli
protein ABCG2, dok je drugi račun obuhvaćao samo mjesto vezanja supstrata i inhibitora (šupljna 1).
Temeljem provedenog računalnog istraživanja vezanja liganada na protein ABCG2 utvrđeno je da
DAC-amidi imaju povoljniji afinitet vezanja za šupljinu 1 od poznatih inhibitora proteina ABCG2.
Spojevi DAC-amidi se za razliku od poznatih inhibitora i supstrata proteina ABCG2 ne vežu duboko
unutar šupljine 1 te ne ostvaruju značajnije interakcije s aminokiselinom koja je literaturno
apostrofirana kao važna za vezanje (Phe 439). Budući da se DAC-amidi također vežu za mjesto prijelaza
iz domene NBD u domenu TMD predložena su dva potencijalna načina inhibicije proteina ABCG2.

Abstract (english)

ABCG2 is a transmembrane protein pump that protects tissue from entrance of unwanted substances.
However, ABCG2 affects the pharmacokinetics of commonly used drugs, and its expression correlates
with poor treatment outcome of certain cancers. Recent studies have revealed that adamantylsubstituted
diaza- (DAC) crown compounds show inhibitory potential towards ABCG2. The aim of this
graduate thesis was to study the binding interactions between DAC crown coumpounds and ABCG2.
To evaluate the binding potential of DAC crown compounds, a study of binding interactions between
known ABCG2 inhibitors and ABCG2 has been made in parallel. The binding interactions were
investigated using two molecular docking simulations. In the first simulation ligands were docked onto
the whole ABCG2 protein whilst in the second simulation ligands were docked into the substrate
binding site (Cavity 1). Results obtained in the scope of this thesis suggest that DAC-amids have lower
binding energy than known inhibitors bound in Cavity 1 and that they also bind to the NBD-TMD
interface. Binding of DAC-amids in Cavity 1 is shallower and they do not interact with Phe 439, which
is literary known to be important for substrate binding. For the reasons stated, two potential ways of
ABCG2 inhibition by DAC-amids have been proposed.

• Keywords: protein ABCG2; krunasti eteri; inhibitori; molekulsko uklapanje
• Keywords (english): ABCG2; crown ethers; inhibitors; molecular docking
• Language: croatian
• URN:NBN: urn:nbn:hr:217:191282
• Study programme: Title: Molecular Biology; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra molekularne biologije (magistar/magistra molekularne biologije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2021-07-22 12:28:37