Компьютерное прогнозирование спектров биологической активности химических соединений: возможности и ограничения

oai:www.bmc-rm.org:article/4An essential characteristic of chemical compounds is their biological activity since its presence can become the basis for the use of the substance for therapeutic purposes, or, on the contrary, limit the possibilities of its practical application due to the manifestation of side action and toxic effects. Computer assessment of the biological activity spectra makes it possible to determine the most promising directions for the study of the pharmacological action of particular substances, and to filter out potentially dangerous molecules at the early stages of research. For more than 25 years, we have been developing and improving the computer program PASS (Prediction of Activity Spectra for Substances), designed to predict the biological activity spectrum of substance based on the structural formula of its molecules. The prediction is carried out by the analysis of structure-activity relationships for the training set, which currently contains information on structures and known biological activities for more than one million molecules. The structure of the organic compound is represented in PASS using Multilevel Neighborhoods of Atoms descriptors; the activity prediction for new compounds is performed by the naive Bayes classifier and the structure-activity relationships determined by the analysis of the training set. We have created and improved both local versions of the PASS program and freely available web resources based on PASS (http://www.way2drug.com). They predict several thousand biological activities (pharmacological effects, molecular mechanisms of action, specific toxicity and adverse effects, interaction with the unwanted targets, metabolism and action on molecular transport), cytotoxicity for tumor and non-tumor cell lines, carcinogenicity, induced changes of gene expression profiles, metabolic sites of the major enzymes of the first and second phases of xenobiotics biotransformation, and belonging to substrates and/or metabolites of metabolic enzymes. The web resource Way2Drug is used by over 19 000 researchers from more than 100 countries around the world, which allowed them to obtain over 600 000 predictions and publish about 500 papers describing the obtained results. The analysis of the published works shows that in some cases the interpretation of the prediction results presented by the authors of these publications requires an adjustment. In this work, we provide the theoretical basis and consider, on particular examples, the opportunities and limitations of computer-aided prediction of biological activity spectra.Важной характеристикой химических соединений является их биологическая активность, поскольку ее наличие может стать основой для использования вещества в терапевтических целях, либо, напротив, ограничить возможности его практического применения вследствие проявления побочных и токсических эффектов. Компьютерная оценка спектра биологической активности дает возможность определить наиболее перспективные направления для тестирования фармакологического действия конкретных веществ и отсеять потенциально опасные молекулы на ранних стадиях исследований. Свыше 25 лет нами осуществляется разработка и совершенствование компьютерной программы PASS (Prediction of Activity Spectra for Substances), предназначенной для прогнозирования спектра биологической активности вещества по структурной формуле его молекул. Прогноз осуществляется на основе анализа зависимостей «структура-активность» для соединений обучающей выборки, в настоящее время содержащей информацию о структурах и известных видах биологической активности более чем для миллиона молекул. Описание структуры молекул органического соединения реализовано в PASS посредством дескрипторов атомных окрестностей (Multilevel Neighborhoods of Atoms), прогнозирование активности для новых соединений выполняется алгоритмом на основе «наивного Байесовского подхода» и зависимостей «структура-активность», выявляемых при анализе обучающей выборки. Нами созданы и совершенствуются как локальные версии программы PASS, так и свободно доступные в Интернет веб-ресурсы на основе PASS (http://way2drug.com): прогноз нескольких тысяч видов биологической активности (фармакологические эффекты, молекулярные механизмы действия, специфическая токсичность и побочное действие, метаболизм, а также влияние на нежелательные мишени, молекулярный транспорт, генную экспрессию), прогноз цитотоксичности для опухолевых и неопухолевых клеточных линий, прогноз канцерогенности, прогноз индуцированных органическими соединениями изменений профилей экспрессии генов, прогноз взаимодействия с ферментами метаболизма лекарств, в том числе прогноз сайтов метаболизма, а также прогноз принадлежности к субстратам и/или метаболитам этих ферментов. Веб-ресурс Way2Drug используют свыше 19 тысяч исследователей более чем из 100 стран мира, что позволило им осуществить свыше 600 тысяч прогнозов и опубликовать около 500 работ с описанием полученных результатов. Анализ опубликованных работ показывает, что в некоторых случаях приводимая авторами этих публикаций интерпретация результатов прогноза требует корректировки. В рамках настоящей работы мы представим теоретическое обоснование и рассмотрим на конкретных примерах возможности и ограничения компьютерного прогнозирования спектров биологической активности

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