ssmuБюллетень сибирской медициныBulletin of Siberian Medicine1682-03631819-3684Siberian State Medical University, the Ministry of Healthcare of the Russian Federation10.20538/1682-0363-2024-4-136-144ssmu-5881Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL PAPERSИсследование молекулярных взаимодействий синтетических глюкокортикоидов с TRPM8 методом молекулярного докингаStudying molecular interactions of synthetic glucocorticoids with TRPM8 by molecular dockinghttps://orcid.org/0000-0001-6655-1049ТимкинП. Д.TimkinP. D.

Тимкин Павел Дмитриевич – аспирант, кафедра химии, 

675001, Амурская обл., г. Благовещенск, ул. Горького, 101 

101, Gorkogo Str., Blagoveshchensk, 675001

timkin.pasha@mail.ruhttps://orcid.org/0009-0003-5159-5796КотельниковД. Д.KotelnikovD. D.

Котельников Данил Дмитриевич – студент 2-го курса, 

675000, Амурская обл., г. Благовещенск, ул. Политехническая, 86

86, Politekhnicheskaya Str., Blagoveshchensk, 675005

danil.kotelnikov.02@mail.ruhttps://orcid.org/0000-0002-3888-2091ТимофеевЭ. А.TimofeevE. A.

Тимофеев Эдуард Андреевич – студент 5-го курса, 

675001, Амурская обл., г. Благовещенск, ул. Горького, 101 

101, Gorkogo Str., Blagoveshchensk, 675001

smileket@inbox.ruhttps://orcid.org/0000-0003-3921-8755НаумовД. Е.NaumovD. E.

Наумов Денис Евгеньевич – канд. мед. наук, зав. лабораторией молекулярных и трансляционных исследований, 

675011, Амурская обл., г. Благовещенск, ул. Калинина, 22 

22, Kalinina Str., Blagoveshchensk, 675011

denn1985@bk.ruhttps://orcid.org/0000-0002-0983-4541БородинЕ. А.BorodinE. A.

Бородин Евгений Александрович – д-р мед. наук, профессор, зав. кафедрой химии,

675001, Амурская обл., г. Благовещенск, ул. Горького, 101

101, Gorkogo Str., Blagoveshchensk, 675001

borodin54@mail.ruАмурская государственная медицинская академия (ГМА)РоссияAmur State Medical AcademyRussian FederationДальневосточный государственный аграрный университет (ГАУ)РоссияFar Eastern State Agrarian UniversityRussian FederationДальневосточный научный центр физиологии и патологии дыхания (ДНЦ ФПД)РоссияFar Eastern Scientific Center for Physiology and Pathology of RespirationRussian Federation202426012025234136144Copyright © Тимкин П.Д., Котельников Д.Д., Тимофеев Э.А., Наумов Д.Е., Бородин Е.А., 20252025Тимкин П.Д., Котельников Д.Д., Тимофеев Э.А., Наумов Д.Е., Бородин Е.А.Timkin P.D., Kotelnikov D.D., Timofeev E.A., Naumov D.E., Borodin E.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://bulletin.ssmu.ru/jour/article/view/5881Цель

Цель: осуществление in silico скрининга взаимодействий синтетических глюкокортикоидов с TRPM8.

Материалы и методы

Материалы и методы. Информация о структуре лигандов была получена из базы данных химических соединений PubChem в sdf-формате. Модель белка TRPM8 загружена из базы данных AlphaFold Protein Structure Database (AlpahaFold ID: AF-Q7Z2QW). Предсказание молекулярных полостей и координат их центров осуществлялось на веб-сервере PrankWeb. Моделирование молекулярного взаимодействия проводили с использованием двух программ: AutoDock (генерация 100 эпох) и MOE (генерация 300 поз).

Результаты

Результаты. В ходе проведения исследования выяснилось, что лиганды образуют стабильные комплексы с TRPM8, но при этом все, кроме беклометазона дипропионата, не взаимодействуют с аминокислотным остатком Tyr745 (ключевой сайт связывания для активации канала). Таким образом, можно полагать, что глюкокортикоиды, вероятнее всего, являются ингибиторами данного ионного канала. Из всех глюкокортикоидов особое внимание было уделено преднизолону, флунизолиду и будесониду, так как результаты молекулярного докинга этих молекул с использованием AutoDock и MOE демонстрируют сопоставимые данные.

Заключение

Заключение. Полученные результаты позволяют взглянуть на терапевтический потенциал данных препаратов в аспекте их использования при лечении холод-индуцированной гиперреактивности дыхательных путей, а также расширяют потенциал их персонализированного применения в терапии бронхиальной астмы и хронической обструктивной болезни легких.

Aim

Aim. To carry out in silico screening of interactions of synthetic glucocorticoids with TRPM8.

Materials and methods

Materials and methods. Information on the structure of the ligands was obtained from the PubChem chemical database in sdf format. The TRPM8 protein model was downloaded from the AlphaFold Protein Structure Database (AlpahaFold ID: AF-Q7Z2QW). Prediction of molecular cavities and coordinates of their centers was carried out on the PrankWeb web server. Modeling of molecular interactions was carried out using AutoDock (generation of 100 epochs) and MOE (generation of 300 poses) software.

Results

Results. The study revealed that the ligands formed stable complexes with TRPM8, but all of them, except for beclomethasone dipropionate, did not interact with the Tyr745 amino acid residue (the key binding site for channel activation). Thus, it can be assumed that glucocorticoids are most likely inhibitors of this ion channel. Of all glucocorticoids, special attention was paid to prednisolone, flunisolide, and budesonide, since the results of molecular docking of these molecules using AutoDock and MOE showed comparable data.

Conclusion

Conclusion. The results obtained provide an insight into the therapeutic potential of these drugs in terms of their use in the treatment of cold-induced airway hyperresponsiveness and also expand the potential for their personalized use in the treatment of bronchial asthma and COPD.

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