Računalno određivanje utjecaja deuteriranja na vezanje liganada na adenozinski A2A receptor

doctoral thesis

• Title (english): Computational study on the effect of deuteration on the ligand binding to the adenosine A2A receptor
• Author: Lucija Hok
• Mentor: Robert Vianello (mentor)
• Committee member: Branimir Bertoša (predsjednik povjerenstva)
• Committee member: Janez Mavri https://orcid.org/0000-0002-0767-6367 (član povjerenstva)
• Committee member: Ivan Kodrin (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2023-06-16, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

Primjenom niza modernih računalnih metoda dobiven je detaljan uvid u interakcije koje antagonist istradefilin ostvaruje s adenozinskim A2A receptorom. Temeljem identifikacije strukturnih elemenata koji najviše doprinose vezanju, dizajnirani su derivati većeg afiniteta. Osim konvencionalnog pristupa koji uključuje uvođenje novih funkcionalnih skupina, primijenjena je i modifikacija deuteriranjem čime je postignuto poboljšano vezanje istradefilina u A2A receptor. U ovom radu izotopna supstitucija predstavlja originalan koncept moduliranja farmakodinamičkih svojstava, a dobiveni rezultati ukazuju na veću učinkovitost istradefilina obogaćenog deuterijem što bi se moglo iskoristiti za poboljšanje njegovog farmakoterapijskog profila u liječenju Parkinsonove bolesti.

Abstract (english)

By utilising a series of modern computational methods, a detailed insight into the interactions of the antagonist istradefylline with the adenosine A2A receptor was obtained. Based on the identification of structural elements that contribute the most to binding, higher affinity derivatives were designed. In addition to the conventional approach that includes the introduction of new functional groups, modification by deuteration was also applied, which achieved improved binding of istradefylline to the A2A receptor. In this work, isotopic substitution represents an original concept of modulating pharmacodynamic properties, and the obtained results indicate a greater efficiency of deuterium-enriched istradefylline, which could be used to improve its pharmacotherapeutic profile in the treatment of Parkinson's disease.

• Keywords: A2A receptor; deuteriranje; istradefilin; Parkinsonova bolest; računalne metode
• Keywords (english): A2A receptor; computational methods; deuteration; istradefylline; Parkinson's disease
• Language: croatian
• URN:NBN: urn:nbn:hr:217:324947
• Promotion: 2023
• Study programme: Title: Doctoral study in chemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija (doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija)
• Type of resource: Text
• Extent: 191 str. ; 30 cm
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2025-06-16
• Created on: 2023-06-28 09:30:11