Istraživanje interakcije spojeva iz masline s tirozin kinazom HGFR/C-MET pomoću molekulskog uklapanja

master's thesis

• Title (english): Study of interactions between olive compounds and tyrosine kinase HGFR/C-MET using molecular docking
• Author: Fran Jagar
• Mentor: Višnja Stepanić (mentor)
• Mentor: Monika Barbarić (mentor)
• Committee member: Višnja Stepanić (predsjednik povjerenstva)
• Committee member: Monika Barbarić (član povjerenstva)
• Committee member: Cvijeta Jakobušić Brala (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry); Zagreb
• Defense date and country: 2023-03-16, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Protein kinaze su enzimi koji kataliziraju proces fosforilacije, poznati su onkogeni i posreduju većini prijenosa signala u eukariotskim stanicama modifikacijom aktivnosti proteinskih supstrata, kontroliranjem mnogih staničnih procesa poput metabolizma, transkripcije gena, progresije staničnog ciklusa, preuređivanja citoskeleta i kretanja stanica, apoptoze i diferencijacije stanica. Glavna uloga kinaza u patofiziologiji bolesti istaknuta je nakon otkrića da mutacije kinaza mogu dovesti do dijabetesa, karcinoma, kardiovaskularnih, neurodegenerativnih, razvojnih i imunosnih poremećaja. Protein kinaze važne su kliničke mete brojnih inhibitora kinaza u kliničkoj praksi te u kliničkim ispitivanjima. Predmet in silico istraživanja ovog diplomskog rada je bio receptor za faktor rasta hepatocita (Hepatocyte growth factor receptor, HGFR) koji je finalni produkt transkripcije (proto-onko) gena MET, a naziva se još i c-Met kinaza. Inhibitorna aktivnost odabranih spojeva iz masline (Olea europea L.) na c-Met kinazi ispitivana je procesom molekulskog uklapanja (program Maestro), jednim od najmodernijih pristupa u ispitivanju potencijalnih novih lijekova. Za potrebe istraživačkog dijela ovog rada formirana je biblioteka od dvije podgrupe spojeva: 17 spojeva koji su poznati inhibitori HGFR/c-Met kinaze i 31 spoj koji se nalaze u maslini (Olea europea L.). Dobiveni rezultati sugerirali su kako bi flavonoidi diosmetin, apigenin, luteolin i kvercetin mogli imati inhibitorni učinak, , što je u skladu s literaturnim podacima. Kao mogući novi ATP-kompetitivni inhibitori kinaze c-Met otkriveni su i lignani berhemol (u 2R, 3S, 4R konfiguraciji), (+)-verukozin i (+)-pinorezinol što bi trebalo potvrditi daljnjim in vitro testiranjem.

Abstract (english)

Protein kinases are enzymes which catalyze the process of phosphorylation, they are known ocogenes and mediate many cellular signaling pathways by modification of substrate activity and controlling many cell processes like metabolism, gene transcription, cell cycle activity, cytoskeletal rearrangement, apoptosis and differentiation. The key role of kinases in disease pathophysiology is underscored by the finding that mutation in kinases can lead to diabetes, cancer, cardiovascular, neurodegenerative, developmental, immune and behavioral disorders. Protein kinases are important clinical targets of numerous kinase inhibitors in clinical use or undergoing clinical trials. The main subject of this study is the kinase Hepatocyte growth factor receptor which is also called c-Met kinase and is the final product of the (proto-onco) gene MET transcription. Molecular docking, which is one of the newest approaches in drug discovery, was used for examination of the potential inhibitory activity of the selected compounds found in olive plant (Olea europea L.) on the c-Met kinase. The group of molecules selected for examination in this study (library) was made of 17 known c-Met kinase inhibitors and 31 compounds found in olive plant (Olea europea L.). The obtained results suggest that the flavonoids diosmetin, apigenin, luteolin and quercetin could have an inhibitory effect, which is in accordance with literature data. As possible novel ATP-competitive inhibitors of c-Met kinase, the lignans berhemol (u 2R, 3S, 4R stereoconfiguration), (+)-verrucosin and (+)-pinoresinol are also discovered, which should be confirmed by further in vitro testing.

• Keywords: rotein kinaze; HGFR; molekulsko uklapanje; c-Met kinaza
• Keywords (english): protein kinases; HGFR; molecular docking; c-Met kinase
• Language: croatian
• URN:NBN: urn:nbn:hr:163:244119
• Study programme: Title: Pharmacy; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: magistar/magistra farmacije (magistar/magistra farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2023-03-16 11:35:36