danДоклады Национальной академии наук БеларусиDoklady of the National Academy of Sciences of Belarus1561-83232524-2431The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1561-8323-2023-67-3-197-206dan-1129Research ArticleХИМИЯCHEMISTRYDe novo дизайн потенциальных ингибиторов основной протеазы коронавируса SARS-CoV-2 с помощью технологий искусственного интеллекта и молекулярного моделированияDe novo design of potential SARS-CoV-2 main protease inhibitors using artificial intelligence and molecular modeling technologiesАндриановА. М.AndrianovA. M.

Андрианов Александр Михайлович – д-р хим. наук, профессор, гл. науч. сотрудник

ул. Купревича, 5/2, 220084, Минск, Республика Беларусь

Andrianov Alexander M. – D. Sc. (Chemisrty), Professor, Chief Researcher

5/2, Kuprevich Str., 220084, Minsk, Republic of Belarus

alexande.andriano@yandex.ruФурсК. В.FursK. V.

Фурс Константин Викторович – инженер-программист

ул. Сурганова, 6, 220012, Минск, Республика Беларусь

Furs Konstantin V. – Software Engineer

6, Surganov Str., 220012, Minsk, Republic of Belarus

ky6ujlo@gmail.comШульдовН. А.ShuldauM. A.

Шульдов Никита Андреевич – инженер-программист

ул. Сурганова, 6, 220012, Минск, РеспубликаБеларусь

Shuldau Mikita A. – Software Engineer

6, Surganov Str., 220012, Minsk, Republic of Belarus

nickshuldov29@gmail.comТузиковА. В.TuzikovA. V.

Тузиков Александр Васильевич – член-корреспондент, д-р физ.-мат. наук, профессор, заведующий лабораторией

ул. Сурганова, 6, 220012, Минск, РеспубликаБеларусь

Tuzikov Alexander V. – Corresponding Member, D. Sc. (Physics and Mathematics), Professor, Head of the Laboratory

6, Surganov Str., 220012, Minsk, Republic of Belarus

tuzikov@newman.bas-net.byИнститут биоорганической химии Национальной академии наук БеларусиInstitute of Bioorganic Chemistry of the National Academy of Sciences of BelarusОбъединенный институт проблем информатики Национальной академии наук БеларусиUnited Institute of Informatics Problems of the National Academy of Sciences of Belarus202306072023673197206Copyright © Андрианов А.М., Фурс К.В., Шульдов Н.А., Тузиков А.В., 20232023Андрианов А.М., Фурс К.В., Шульдов Н.А., Тузиков А.В.Andrianov A.M., Furs K.V., Shuldau M.A., Tuzikov A.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://doklady.belnauka.by/jour/article/view/1129

С помощью генеративной нейронной сети глубокого обучения, разработанной ранее на основе технологий искусственного интеллекта, осуществлен de novo дизайн 95 775 потенциальных лигандов основной протеазы (Mpro) SARS-CoV-2, играющей важную роль в процессе репликации вируса. Методами молекулярного докинга и молекулярной динамики выполнена оценка аффинности связывания этих молекул с каталитическим сайтом фермента. В результате проведенных исследований отобраны 7 соединений-лидеров, которые характеризуются низкими значениями свободной энергии Гиббса, сопоставимыми с величинами, полученными с помощью идентичного вычислительного протокола для двух мощных нековалентных ингибиторов Mpro SARS-CoV-2, использованных в расчетах в качестве позитивного контроля. Полученные результаты свидетельствуют о перспективности использования идентифицированных соединений в работах по созданию новых противовирусных препаратов, терапевтическое действие которых основано на ингибировании каталитической активности Mpro SARS-CoV-2.

De novo design of 95 775 potential ligands of SARS-CoV-2 main protease (Mpro), playing an important role in the process of virus replication, was carried out using a deep learning generative neural network that was developed previously based on artificial intelligence technologies. Molecular docking and molecular dynamics methods were used to evaluate the binding affinity of these molecules to the catalytic site of the enzyme. As a result, 7 leading compounds exhibiting Gibbs free energy low values comparable with the values obtained using an identical computational protocol for two potent non-covalent SARS-CoV-2 Mpro inhibitors used in calculations as a positive control were selected. The results obtained indicate the promise of applying identified compounds for development of new antiviral drugs able to inhibit the catalytic activity of SARSCoV-2 Mpro.

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The authors declare that there are no conflicts of interest present.