Računalniško načrtovanje dualnih zaviralcev za zdravljenje Alzheimerjeve bolezni

Arnež, Ana (avtor), Gobec, Stanislav (mentor), Proj, Matic (komentor)

Pri magistrski nalogi smo računalniško načrtovali dualne zaviralce butirilholinesteraze in z mitogenom aktivirane protein kinaze p38α za zdravljenje Alzheimerjeve bolezni. Ta bolezen je pereč problem v razvitih državah, kjer se daljša življenjska doba. Trenutno zdravljenje poteka z zaviralci acetilholinesteraze, ki pa ima lahko prisotne neželene stranske učinke. Raziskave so pokazale, da bi selektivni zaviralci butirilholinesteraze bolje učinkovali pri zdravljenju Alzheimerjeve bolezni, saj glede na njeno fiziološko vlogo predvidevajo, da bi tovrstni zaviralci imeli manj neželenih stranskih učinkov. Del patogeneze Alzheimerjeve bolezni je vnetje nevronov, kar bi lahko preprečili zaviralci z mitogenom aktivirane protein kinaze p38α. S sidranjem dobavljivih znanih zaviralcev z mitogenom aktivirane protein kinaze p38α v aktivno mesto butirilholinesteraze smo glede na naše kriterije izbrali enajst spojin za naročilo. Z biokemijskem testiranjem smo potrdili aktivnost ene spojine, MPB01, na obeh tarčah. MPB01 je zavirala butirilholinesterazo v nizkem mikromolarnem območju in z mitogenom aktivirane protein kinaze p38α v nanomolarnem območju. Poleg tega je selektivno zavirala butirilholinesterazo v primerjavi z acetilholinesterazo. Spojino smo sidrali v aktivno mesto obeh tarč in pripravili več farmakofornih modelov za naslednjo stopnjo virtualnega rešetanja. Validacijo modelov smo izvedli s knjižnico biokemijsko ovrednotenih spojin na obeh tarčah, ki smo jih ustrezno razdelili na aktivne in neaktivne spojine. Knjižnici neaktivnih spojin smo dodali tudi računalniško generirane neaktivne spojine. Glede na rezultate validacije smo izbrali en farmakoforni model, s katerim smo filtrirali knjižnico vseh dobavljivih spojin. Zadetke smo sidrali v aktivno mesto obeh tarč, zožili izbor spojin glede na cenilno funkcijo in raznolikost, ter izbrali enaindvajset spojin za naročilo. Med izbranimi nobena spojina ni izkazovala izboljšane aktivnosti glede na prvotni zadetek, ki predstavlja dobro izhodišče za nadaljnji razvoj dualnih zaviralcev za zdravljenje Alzheimerjeve bolezni.

• Jezik: Slovenski jezik
• Ključne besede: butirilholinesteraza, z mitogenom aktivirane protein kinaze p38α, Alzheimerjeva bolezen, računalniško načrtovanje, virtualno rešetanje
• Vrsta gradiva: Magistrsko delo/naloga
• Tipologija: 2.09 - Magistrsko delo
• Organizacija: FFA - Fakulteta za farmacijo
• Leto izida: 2022
• PID: 20.500.12556/RUL-141192
• Datum objave v RUL: 24.09.2022

ARNEŽ, Ana, 2022, Računalniško načrtovanje dualnih zaviralcev za zdravljenje Alzheimerjeve bolezni [na spletu]. Magistrsko delo. [Dostopano 8 april 2025]. Pridobljeno s: https://repozitorij.uni-lj.si/IzpisGradiva.php?lang=slv&id=141192

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Computational design of dual inhibitors for the treatment of Alzheimer's disease

Izvleček

In the Master's thesis, we computationally designed dual inhibitors of butyrylcholinesterase and mitogen-activated protein kinase p38α for the treatment of Alzheimer's disease. This disease is a pressing problem in developed countries where life expectancy is increasing. Current treatment is with acetylcholinesterase inhibitors, which can have undesirable side effects. Research has shown that selective butyrylcholinesterase inhibitors would be more effective in the treatment of Alzheimer's disease, because given its physiological role, they predict that such inhibitors would have fewer unwanted side effects. Part of the pathogenesis of Alzheimer's disease is neuroinflammation, which could be prevented by inhibitors of mitogen-activated protein kinase p38α. With molecular docking of commercially available known inhibitors of mitogen-activated protein kinase p38α into the active site of butyrylcholinesterase, we selected eleven compounds for ordering according to our criteria. Biochemical assay confirmed the activity of one compound, MPB01, on both targets. MPB01 inhibited butyrylcholinesterase in the low micromolar range and mitogen-activated protein kinase p38α in the nanomolar range. In addition, it selectively inhibited butyrylcholinesterase compared to acetylcholinesterase. We docked the compound in the active site of both targets and prepared several pharmacological models for the next stage of virtual screening. Validation of the models was carried out with a library of biochemically evaluated compounds on both targets, which were appropriately divided into a set of active and a set of inactive compounds. We also added computationally generated decoys to the library of inactive compounds. Based on the validation results, we selected one pharmacophore model for filtering of the library of all stock compounds. We docked the hits to the active site of both targets, narrowed the selection of compounds based on scoring function and diversity, and selected twenty-one compounds for ordering. Among the selected compounds, no compound showed improved activity compared to the original hit, which represents a good starting point for the further development of dual inhibitors for the treatment of Alzheimer’s disease.

• Ključne besede: butyrylcholinesterase, p38α mitogen-activated protein kinase, Alzheimer’s disease, computational design, virtual screening