Vrednotenje uporabnosti metod in silico pri napovedovanju nevrotoksičnosti, razvojne nevrotoksičnosti in teratogenosti izbranih topil

Harinski, Tjaša (author), Sollner Dolenc, Marija (mentor)

Topilom smo ljudje vsak dan zelo izpostavljeni. Pomembno je, da se zavedamo, da ima vsako topilo, tako kot druge snovi, potencialne toksične učinke ne samo na ljudi, ampak tudi na ostali živi svet ter na okolje okoli nas. V magistrski nalogi smo z metodami in silico vrednotili nevrotoksičnost, razvojno nevrotoksičnost ter teratogenost izbranih topil. Pridobljene podatke za izbrano bazo topil smo primerjali z v podatkovnih bazah pridobljenimi že znanimi in vivo ter in vitro literaturnimi podatki. Raziskovati smo začeli s pomočjo orodij in silico, ki bi v prihodnosti lahko nadomestila ali pa vsaj zmanjšala število raziskav in vivo ter in vitro. Za delo smo izbrali validiran računalniški program Derek Nexus, ki se v začetnih stopnjah razvoja zdravilnih učinkovin (ZU) uporablja za napovedovanje potencialne toksičnosti snovi. V raziskavo smo vključili 244 topil. Derek Nexus snovi kot verjetno toksične prepozna oz. kategorizira na podlagi strukturnih značilnosti molekule ti. toksoforne skupine, ki predstavlja tvegani strukturni element spojine, odgovoren za njen toksični učinek. Napoved je podkrepljena z grafično obrazložitvijo razmerja med strukturo in delovanjem (SAR), s podatki o toksičnosti spojin znotraj SAR, ključnimi referencami in mehanizmi delovanja. Verjetnost toksičnosti za izbrane končne točke je program zaznal pri 40 topilih. V veliki večini primerov je snovi prepoznal kot teratogene (33 topil). Najmanj topil je prepoznal kot razvojno nevrotoksične (2 topili). Kot nevrotoksične pa je napovedal 5 topil. Za vseh 244 topil smo po testiranju in silico za že znane podatke preiskali še podatkovne baze PubChem, PubMed, ScienceDirect ter toksikološke profile spojin. Za izbor že znanih podatkov smo pregledali članke, ki so bili objavljeni od leta 2010 dalje. Po pregledu izbranih podatkovnih baz za literaturne podatke smo, s pomočjo smernic Organizacije za gospodarsko sodelovanje in razvoj (OECD) validacije računskih modelov, ovrednotili napovednost orodja in silico. Ta je dobra, saj so rezultati za točnost več kot 70 %, z vidika specifičnosti pa skoraj 90 % zanesljivi. Manj zanesljivo program sicer napove biološko aktivne spojine. Podoben trend rezultatov smo dobili tudi pri izbranih končnih točkah. Na koncu smo izpostavili še topila, za katera bi zaradi pridobljenih rezultatov, predlagali podrobnejše analize toksičnosti izbranih končnih točk. Osredotočili smo se na topila, pri katerih smo dobili le rezultate in silico. Za topila, pri katerih smo dobili le literaturne podatke, in pa topila, pri katerih smo dobili tako in silico kot tudi literaturne podatke, smo ocenili, da so z vidika končnih točk dobro raziskana.

• Language: Slovenian
• Keywords: topilo, nevrotoksičnost, razvojna nevrotoksičnost, teratogenost, metode in silico, Derek Nexus
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2021
• PID: 20.500.12556/RUL-127964
• Publication date in RUL: 30.06.2021

Secondary language

• Language: English
• Title: Evaluation of in silico tools used for prediction of neurotoxicity, developmental neurotoxicity and teratogenicity of selected solvents

Abstract

Exposure to solvents on a daily base is higher than we think. It is important to be aware that each solvent, like any other substance, has potential toxic effects not only on humans but also on the rest of the living world and the environment. In the master's thesis, we evaluated neurotoxicity, developmental neurotoxicity and teratogenicity of selected solvents using methods in silico. The obtained data for the selected solvent database were compared with the already known in vivo and in vitro literature data obtained in databases. We undertook the research with the help in silico tools that could replace or at least reduce the number of in vivo and in vitro researches in the future. We selected the validated Derek Nexus computer program for the work, which is used in the early stages of drug development to predict the potential toxicity of a substance. In the task, 244 solvents were examined. Derek Nexus recognizes substances as probable toxins on the structural characteristics of the molecule; toxicophoric groups representing a hazardous structural element of a compound responsible for its toxic effect. The prediction is supported by a graphical explanation of the relationship between structure and action (SAR), data on the toxicity of the compounds within the SAR, key references and and mechanisms of action. Possible toxicity for selected endpoints was detected by the program at 40 solvents. In the vast majority of cases, the substance was identified as teratogenic (33 solvents). Least solvents as developmental neurotoxic (2 solvents). As neurotoxic, however, he predicted 5 solvents. For all 244, we also examined PubChem, PubMed, ScienceDirect databases and toxicological profiles of compounds for already known data. For the purposes of the thesis, we selected articles published from 2010. After reviewing selected databases for literature data, we evaluated the predictability of the tool and silica with the help of the OECD guidelines for the validation of accounting. The predictability of the program is good. A similar trend was obtained at selected endpoints. Finally, we pointed out the solvents for which, due to the obtained results, we would suggest more detailed toxicity analyzes of the selected endpoints. We focused on solvents in which we obtained only in silico results. For solvents for which only literature data were obtained and for solvents for which both in silico and literature data were obtained, they were estimated to be well known in terms of endpoints.

• Keywords: solvent, neurotoxicity, developmental neurotoxicity, teratogenicity, methods in silico, Derek Nexus