Vrednotenje vezave bisfenolov na estrogenski receptor alfa s farmakofornimi modeli in virtualnim rešetanjem

Iskra, Anamarija (author), Peterlin Mašič, Lucija (mentor), Toplak, Žan (comentor)

Bisfenol A ali BPA je najbolj znan predstavnik skupine bisfenolov. Mehanizem njegovega vpletanja v delovanje endokrinega sistema preko estrogenskega receptorja alfa (ERα) je dobro raziskan in predstavlja osnovo številnih regulatornih omejitev uporabe BPA. V industriji plastike zato narašča uporaba analogov BPA, ki so veliko manj raziskani ter jih regulatorne omejitve zajemajo zgolj v manjši meri. Na podlagi strukturne podobnosti spojin z BPA imajo njegovi analogi potencial tudi za podobne toksične učinke na endokrini sistem. V okviru magistrske naloge smo s pomočjo metod virtualnega rešetanja s farmakofornimi modeli ter molekulskega sidranja proučevali vezavo 38 izbranih analogov BPA v ERα. V programu LigandScout smo pripravili farmakoforne modele na podlagi strukture ligandov in na podlagi strukture vezavnih mest ERα izbranih PDB kristalnih struktur ter jih ovrednotili z virtualnim rešetanjem s knjižnicami aktivnih ter neaktivnih spojin na ERα. Modeli, ki temeljijo na strukturi vezavnega mesta, so pričakovano pokazali večjo napovedno vrednost vezave preiskovanih spojin v ERα. Molekulsko sidranje smo izvedli s pomočjo programskega orodja AutoDock Vina v vezavnih žepih štirih izbranih kristalnih struktur 3UU7, 3UUA, 3UUC in 3UUD. Za rezultate ovrednotenja farmakofornih modelov v obliki vrednosti ujemanja s farmakofornim modelom (VUFM), ki opisuje ujemanje interakcij spojine s farmakofornimi elementi, ter rezultate sidranja v obliki internega parametra afinitete (kcal/mol), smo preverili korelacijo z biološkimi literaturnimi vrednostmi o jakosti vezave spojin ter in vitro pridobljenimi vrednostmi na Fakulteti za farmacijo. Omenjene vrednosti ne nakazujejo dobre korelacije, ocena slednje je težavna in nezanesljiva zaradi majhnega razpona ter pomanjkanja literaturnih podatkov o jakosti vezave spojin na ERα. V drugem delu naloge smo pripravljene farmakoforne modele in molekulsko sidranje uporabili za analizo spojin, ki so povezane s proizvodnjo plastike. Podatki o spojinah so povzeti po članku z naslovom: Overview of known plastic packaging-associated chemicals and their hazards. Oba uporabljena pristopa analize, molekulsko sidranje in rešetanje s farmakofornimi modeli, sta se pri identifikaciji bisfenolov in spojin s podobno strukturo enakovredno izkazala. Večina spojin iz strukturnih razredov bisfenolov in sorodnih spojin se glede na zbrane podatke iz članka uvršča med motilce endokrinega sistema (EDC). Izmed spojin, ki smo jim z molekulskim sidranjem in tudi s farmakofornimi modeli napovedali potencialno aktivnost na ERα ter hkrati še niso identificirane kot EDC, smo pripravili seznam spojin, ki so zanimive za nadaljnje raziskovanje zaradi njihovega potenciala, da delujejo kot EDC.

• Language: Slovenian
• Keywords: bisfenoli, motilci endokrinega sistema, virtualno rešetanje, farmakoforni modeli, molekulsko sidranje
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2021
• PID: 20.500.12556/RUL-132819
• Publication date in RUL: 04.11.2021

ISKRA, Anamarija, 2021, Vrednotenje vezave bisfenolov na estrogenski receptor alfa s farmakofornimi modeli in virtualnim rešetanjem [online]. Master’s thesis. [Accessed 14 April 2025]. Retrieved from: https://repozitorij.uni-lj.si/IzpisGradiva.php?lang=eng&id=132819

Secondary language

• Language: English
• Title: Evaluation of bisphenol binding to estrogen receptor alpha by pharmacophore models and virtual screening

Abstract

Bisphenol A or BPA is best-known substance in the bisphenol group. Its activity as endocrine disrupting chemical on the estrogen receptor alpha (ERα) is well researched and forms the basis of many regulatory restrictions on the use of BPA. In the plastics industry, consequently, the use of BPA analogues as BPA alternatives is increasing as they are not yet part of the regulatory limitations and their activity in the human body has not yet been clarified. Based on the structural similarities to BPA, analogues also have the potential for similar endocrine system toxicity. In this master's thesis, we studied the binding of 38 selected BPA analogues to the ERα using virtual screening on pharmacophore models and molecular docking. In the LigandScout software, we prepared ligand-based and structure-based pharmacophore models and evaluated them by virtual screening with libraries containing active compounds and decoys on ERα. As expected, higher predictive value of the binding of the compounds investigated to ERα was obtained by structure-based pharmacophore models. Molecular docking was performed in the binding pockets of four Protein Data Bank crystal structures (3UU7, 3UUA, 3UUC, 3UUD) using the AutoDock Vina software. We examined the correlation among literature values on compound potency on ERα, in vitro values obtained at the Faculty of Pharmacy together with Pharmacophore-Fit score and affinity that represented the results of evaluation of pharmacophore modeling and molecular docking, respectively. These values do not indicate a good correlation, the assessment of the latter is difficult and unreliable due to the low range and lack of literature data on the potency of compounds. In the second part of master's thesis, we used prepared pharmacophore models and molecular docking to analyze compounds related to plastics production. Information on compounds is collected from the article entitled: Overview of known plastic packaging-associated chemicals and their hazards. Both in silico methods, pharmacophore modeling and molecular docking showed comparable ability to identify bisphenols and compounds with similar structure. Most substances in the structural classes of bisphenols and related compounds are classified as endocrine disruptors according to the data collected in the article. We have classified all the compounds to which we have predicted potential activity on ERα using molecular docking and pharmacophore modeling and are not yet identified as hormone disruptors. We have prepared a list of compounds that are of interest for further research due to their potential to act as endocrine disrupting chemicals (EDC).

• Keywords: bisphenols, endocrine disrupting chemicals, virtual screening, pharmacophore modeling, molecular docking