20.500.12556/DKUM-97522 Raziskovanje antikarcinogenih učinkov polifenolov iz smilja kot inhibitorjev Pim-1 kinaze diplomsko delo univerzitetnega študijskega programa I. stopnje Studying the anticancer effects of polyphenols from Helichrysum as inhibitors of Pim-1 kinase V diplomskem delu je opisano raziskovanje polifenolov iz smilja kot inhibitorjev Pim-1 kinaze. Pim-1 kinaza igra pomembno vlogo pri rasti in razvoju raka ter je zato prepoznana kot terapevtska tarča pri zdravljenju raka. Med obetavne inhibitorje Pim-1 kinaze spada tudi skupina polifenolov, imenovana flavonoidi, ki se izkazujejo med drugimi tudi z antikarcinogenimi lastnostmi. Flavonoidi se najdejo v cvetovih rastline smilj, ki raste v Mediteranu in se njegovi ekstrakti se ponašajo z zdravilnimi učinki. Po pregledu znanstvene literature o smilju smo tabelirali izstopajoče spojine s potencialnimi antikarcinogenimi učinki. S CmDock vtičnikom programa PyMOL smo izvedli molekulsko sidranje, s čimer smo pridobili podatke o učinkovitosti sidranja posamezne spojine. Izstopal je flavonoid kaempferol, s katerim smo posledično nadaljevali raziskovanje. Pripravili smo sistem protein-ligand za simulacijo molekulske dinamike in ga izvedli na superračunalniku Vega. Dobljene rezultate smo analizirali s programoma VMD ter PyMOL, pri čemer smo se osredotočili na analizo strukture kompleksov, RMSD analize, graf energij vezave ter na tvorbo vodikovih vezi. Analizi struktur kompleksov je pokazala uspešno vezavo liganda v aktivno mesto proteina, pri čemer so bile opažene manjše spremembe v orientaciji liganda v primerjavi s strukturo kompleksa pri molekulskem sidranju. RMSD analiza je pokazala stabilnost kompleksa z manjšimi nihanji liganda proti koncu simulacije. Stabilnost kompleksa je potrdil tudi graf energij vezave, analiza vodikovih vezi pa je pokazala, da ligand tvori le eno stabilno vodikovo vez s proteinom. Za konec smo izračunali še vrednost vezavne proste energije in inhibicijsko konstanto kaempferola na aktivno mesto Pim-1 kinaze. Dobljene vrednosti so pokazale, da kaempferol izkazuje šibko inhibicijo Pim-1 kinaze. Analize simulacije molekulske dinamike so pokazale, da ligand kaže na večjo mobilnost pri vezavi na aktivno mesto proteina in ne vzpostavi močne mreže stabilnih interakcij s proteinom. Izračunana vrednost inhibicijskega potenciala je tudi potrdila opažanja analiz. Nadaljnje primerjave rezultatov s preteklimi raziskavami so nakazale, da kvercetin in naringenin izkazujeta večji potencial za inhibicijo Pim-1 kinaze, saj tvorita bolj stabilen kompleks protein-ligand z večimi vodikovimi vezmi. Zaključili smo, da smilj še vedno ostaja obetavna rastlina za nadaljnje raziskave, saj poleg kaempferola vsebuje tudi omenjen naringenin ter v manjših količinah tudi kvercetin. Poudarili smo tudi pomen uporabe različnih dinamičnih metod pri ocenjevanju inhibitornega potenciala ligandov. The thesis describes the investigation of polyphenols from Helichrysum as inhibitors of Pim-1 kinase. Pim-1 kinase plays an important role in cancer growth and development and is therefore recognized as a therapeutic target in cancer treatment. Among the promising inhibitors of Pim-1 kinase is a group of polyphenols called flavonoids, which are also known for their anticarcinogenic properties. Flavonoids can be found in the flowers of the Helichrysum plant, which grows in the Mediterranean region, and whose extracts are known for their medicinal effects. After reviewing the scientific literature on Helichrysum, we tabulated the most prominent compounds with potential anticarcinogenic effects. Using the CmDock plugin for the PyMOL software, we performed molecular docking to obtain data on the docking efficiency of each compound. The flavonoid kaempferol stood out, and we therefore continued our research with it. A protein–ligand system was prepared for molecular dynamics simulation and executed on the Vega supercomputer. The obtained results were analyzed using the VMD and PyMOL programs, focusing on the analysis of complex structures, RMSD analysis, binding energy graphs, and the formation of hydrogen bonds. The structural analysis of the complexes showed successful binding of the ligand in the active site of the protein, although minor changes in the ligand orientation were observed compared to the complex structure obtained during molecular docking. The RMSD analysis demonstrated the stability of the complex, with minor fluctuations of the ligand toward the end of the simulation. The stability of the complex was also confirmed by the binding energy graph, while the hydrogen bond analysis showed that the ligand forms only a single stable hydrogen bond with the protein. Finally, we calculated the binding free energy value and the inhibition constant of kaempferol at the active site of Pim-1 kinase. The obtained values indicated that kaempferol exhibits weak inhibition of Pim-1 kinase. The molecular dynamics simulation analyses showed that the ligand displays higher mobility when bound to the active site of the protein and does not establish a strong network of stable interactions with the protein. The calculated inhibition potential also confirmed the observations from the analyses. Further comparison of the results with previous studies suggested that quercetin and naringenin exhibit a greater potential for inhibiting Pim-1 kinase, as they form a more stable protein–ligand complex with multiple hydrogen bonds. We concluded that Helichrysum remains a promising plant for further research, as in addition to kaempferol it also contains naringenin and, in smaller amounts, quercetin. We also emphasized the importance of using different dynamic methods when evaluating the inhibitory potential of ligands. Pim-1 kinaza kaempferol molekulsko sidranje molekulska dinamike LIE metoda Pim-1 kinase kaempferol molecular docking molecular dynamics LIE method true true false [L. Rozman] Slovenski jezik Angleški jezik Diplomsko delo/naloga 2026-03-15 19:09:41 2026-05-04 08:54:01 2026-05-06 03:07:03 0000-00-00 00:00:00 2026 0 Maribor 0 Maribor 1 spletni vir (1 datoteka PDF (XI, 39 str.)) 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.277.3:547.56(043.2) 277056771 UN_Rozman_Luka_2026.pdf UN_Rozman_Luka_2026.pdf 1 552D81B75B692307634C307CB4D376A2 3a0439c215b827426fcbba247cc1cfe4cd7c74045616b1466989011ce9a23847 da5354b9-42d7-11f1-b28d-00155d0001a1 https://dk.um.si/Dokument.php?lang=slv&id=205662 Fakulteta za kemijo in kemijsko tehnologijo 0 0 0