Ocena interakcij med jedrnimi receptorji in flavonoidi ter izoflavonoidi z metodo in silico

Cerar, Anita (author), Sollner Dolenc, Marija (mentor)

V zadnjih letih je vedno bolj v ospredju raziskovanje vpliva potencialnih kemičnih motilcev endokrinega sistema (KMES) na delovanje endokrinega sistema. Škodljivi učinki KMES pa predstavljajo tudi velik javnozdravstveni problem. Znanstveniki in regulatorni organi se trudijo vzpostaviti testne sisteme, s katerimi bi hitro in zanesljivo lahko preverili ali določena snov deluje kot KMES. V ospredju znanstevnih raziskav so predvsem KMES sintetičnega izvora, mi pa smo se osredotočili na učinke v naravi prisotnih flavonoidov (FL) in izoflavonoidov (IFL). Smernice, za napovedoanje endokrinih učinkov snovi, ki sta jih junija 2018 predstavili Evropska komisija za kemikalije (ECHA) in Evropska agencija za varnost hrane (EFSA) priporočajo uporabo programskih orodij za preverjanje tovrstne aktivnosti spojin. Med omenjenimi programskimi ordji je tudi program Endocrine Disruptome (ED), ki omogoča napovedovanje interakcij z endokrinimi hormonskimi receptorji. ED omogoča sidranje ene spojine hkrati v aktivna mesta 16 struktur, ki pripadajo 12 različnim humanim jedrnim receptorjem. Pri našem delu smo s pomočjo programa ED izvedli sidranje 43 FL in 40 IFL. Rezultate, ki smo jih pridobili s pomočjo programa ED smo primerjali s podatki o potencialnih interakcijah med spojinami in jedrnimi receptorji iz strokovne literature. ED med izbranimi flavonoidi in izoflavonoidi ni vedno pravilno napovedal vezavo tistih spojin, ki so že biološko ovrednotene, in za katere so podatki v strokovni literaturi dostopni. Za IFL ekvol je napačno napovedal vezavo, za 6 IFL in 4 FL pa vezave ni predvidel. Med izbranimi flavonoidi in izoflavonoidi obstajajo tudi takšni, za katere je program ED napovedal visoko afiniteto vezave vsaj na enega izmed preučevanih receptorjev, za katere do zdaj objavljene znanstvene raziskave teh interakcij še niso opisale. Takšnih je 22 FL in 20 IFL. Med izbranimi flavonoidi in izoflavonoidi pa obstajajo tudi 5 FL in 7 IFL, za katere program ED ni napovedal vezave na nobenega od izbranih jedrih receptorjev. ED je primer metode in silico, ki je enostavna za uporabo, s pomočjo katere sklepamo na afiniteto vezave z JHR. Pomanjkljivost programa ED pa je, da ne upošteva drugih interakcij, ki jih FL in IFL imajo v biološkem sistemu. Zaradi pomanjkanja podatkov iz strokovne literature žal ne moremo statistično ovrednotiti napovedne moči ED za možne interakcije med izbranimi FL in IFL ter izbranimi jedrnimi receptorji. Pri interpretaciji pridobljenih rezultatov pa se moramo tudi zavedati, da je delovanje spojin vključno s potencialnimi kemičnimi endokrinimi motilci in vivo zelo kompleksno, zato težko zgolj z metodo in silico določimo obnašanje spojin v bioloških sistemih.

• Language: Slovenian
• Keywords: Endocrine Disruptome, flavonoidi, izoflavonoidi, kemični motilci endokrinega sistema, jedrni hormonski recetptorji, metode in silico
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2020
• PID: 20.500.12556/RUL-113753
• Publication date in RUL: 31.01.2020

Secondary language

• Language: English
• Title: In sillico assessment of flavonoid and isoflavonoid interaction with nuclear receptors

Abstract

In recent years, research of the impact of potential chemical endocrine disruptors (KMES) on endocrine function is on the rise. The adverse effects of KMES are also a major public health problem. Scientists and regulatory authorities are working to establish test systems that can quickly and reliably verify that a substance is acting as a hormone disruptor. The main focus of scientific research is on hormonal disruptors of synthetic origin while we have focused on the naturally occurring flavonoids (FL) and isoflavonoids (IFL). The Guidelines for the Prediction of Endocrine Effects of Substances presented by the European Chemicals Commission (ECHA) and the European Food Safety Authority (EFSA) in June 2018 recommend the use of software tools to check this activity of the compounds. Among these software tools is the Endocrine Disruptome (ED) program, which predics interactions with endocrine hormonal receptors. ED allows anchoring of one compound at a time to the active sites of 16 structures belonging to 12 different human nuclear receptors. In our work, we have anchored 43 FL and 40 IFL using the ED program. The results obtained with the ED program were compared with data on potential interactions between compounds and core receptors in the scientific literature. The ED did not always correctly predict the binding of those compounds that have already been bioassayed and for which data are available in the literature. It incorrectly predicted binding for IFL equol, but did not predict binding for 6 IFL and 4 FL. Among the selected Fl and IFL, there are those for which the ED program has predicted a high binding affinity for at least one of the receptors studied, for which the published scientific studies have not yet described these interactions. There are 22 FL and 20 IFL. Among the selected FL and IFL however, there are 5 FL and 7 IFL for which the ED program did not predict binding to any of the selected core receptors. ED is an example of an easy-to-use method in silico that infers the binding affinity of JHR. The disadvantage of the ED program is that it does not take into account the other interactions that FL and IFL have in the biological system. Unfortunately, due to the lack of data from the scientific literature, we cannot statistically evaluate the predictive power of ED to predict the interactions between selected FL and IFL and selected core receptors. However, when interpreting the results obtained, one must also be aware that the activity of the compounds, including potential chemical endocrine disruptors, is very complex in vivo, so it is difficult to determine the behavior of the compounds in biological systems by method in silico alone.

• Keywords: Endocrine Disruptome, flavonoid, isoflavonoid, chemical endocrine disruptors, nuclear hormone receptor, method in silico