Karakterizacija sulfonilureja biomimetičkom kromatografijom i računalnim metodama

master's thesis

• Title (english): Characterization of sulfonylureas by biomimetic chromatography and computational methods
• Author: Martina Rajić
• Mentor: Ernest Meštrović (mentor)
• Committee member: Nikola Cindro (predsjednik povjerenstva)
• Committee member: Ernest Meštrović (član povjerenstva)
• Committee member: Iva Juranović Cindrić (član povjerenstva)
• Committee member: Ivica Đilović (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2022-09-26, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

Svakim danom se istražuju nove i naprednije metode za određivanje farmakodinamičkih i farmakokinetičkih
parametara u svrhu dizajna novih lijekova. Jedne od modernih metoda su biomimetička kromatografija u kojoj se
koriste kolone koje imitiraju biološke uvjete te računalne (in silico) metode koje predviđaju razne ADME
(Adsorpcija, Distribucija, Metabolizam, Ekskrecija) i QSPR (Kvantitativni odnos strukture i svojstava molekule)
parametre. U ovom radu provedena je karakterizacija tri (3) sulfonilureje ((N-metilkarbamoil)-4-
metilbenzosulfoamid, N-(benzilkarbamoil)-4-metilbenzosulfoamid, 1,1’-trimetilenbis[3-p-tolilsulfonil)-urea]))
biomimetičkom kromatografijom pri čemu se eksperimentalno odredila lipofilnost, fosfolipofilnost te vezanje na
AGP (α-1-kiseli glikoprotein) i HSA (humani serumski albumin) proteine plazme. Računalnim programima
predviđena su različita svojstva poput topljivosti, lipofilnosti, fosfolipofilnosti, vezanja na proteine plazme,
koeficijenta distribucije, oralne bioraspoloživosti, gastrointestinalne apsorpcije i sukladnosti sa Lipinskijevim
pravilom „broja pet“. Za parametre za koje je bilo moguće, napravljena je korelacija eksperimentalno dobivenih
vrijednosti sa računalno izračunatim vrijednostima.
Rezultati analize biomimetičkom kromatografijom pokazuju kako su sve tri sulfonilureje lipofilne, stupaju u
interakciju sa fosfolipidima te se vežu na AGP i HSA proteine plazme. Računalnim programima dobivene su
relativno dobre vrijednosti svojstava koje spoj mora slijediti da bi bio dobar lijek. Za većinu računalno
izračunatih parametara koje je bilo moguće korelirati sa eksperimentalnim vrijednostima dobiven je visok
koeficijent korelacije (R2>0,9). Naposljetku, rezultati eksperimentalnih i računalno dobivenih vrijednosti za
ispitane parametre su vrlo korisne u daljnjem istraživanju analiziranih sulfonilureja kao potencijalnih lijekova.

Abstract (english)

New and more advanced methods of determining pharmacodynamic and pharmacokinetic parameters are being
researched daily for the purpose of drug design. Examples of the modern methods are biomimetic
chromatography which uses columns that mimic biological conditions and computer (in silico) methods that
predict various ADME (Adsorption, Distribution, Metabolism, Elimination) and QSPR (Quantitative StructureProperty Relationship) parameters. In this research, three (3) sulfonylureas (N-methylcarbamoyl)-4-
methylbenzenesulfonamide, N- benzylcarbamoyl)-4-methylbenzenesulfonamide, 1,1’-trimethylenebis[3-(ptolylsulfonyl)-urea]) were characterized by biomimetic chromatography to determine lipophilicity,
phospholipophilicity and binding to AGP (α-1-acid glycoprotein) and HSA (human serum albumin) plasma
proteins. Computer programs were used to predict properties such as solubility, lipophilicity,
phospholipophilicity, protein plasma binding, distribution coefficient, oral bioavailability, gastrointestinal
absorption, and compliance with Lipinski’s “rule of five”. For the parameters for which it was possible, the
experimentally obtained values were correlated with the computer calculated values.
The results of biomimetic chromatography analysis showed that all three sulfonylureas are lipophilic, interact
with phospholipids, and bind to AGP and HSA plasma proteins. Computer programs predicted relatively good
values of the properties that the compound must follow in order to be a good drug. For most of the computercalculated parameters that could be correlated with the experimental values a high correlation coefficient
(R2>0,9) was obtained. Finally, the results of experimental and computer obtained values for the tested
parameters are very useful in further research of the analyzed sulfonylureas as potential drugs.

• Keywords: ADME; biomimetička kromatografija; in silico; lijekovi; računalne metode; sulfonilureja; QSPR
• Keywords (english): ADME; biomimetic chromatography; computational methods; drugs; in silico; sulfonylurea; QSPR
• Language: croatian
• URN:NBN: urn:nbn:hr:217:895495
• Study programme: Title: Graduate university studies in chemistry; specializations in: Research programme; Course: Research programme; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra kemije (magistar/magistra kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2024-09-26
• Created on: 2022-10-13 14:40:01