farmaecFARMAKOEKONOMIKA. Modern Pharmacoeconomics and PharmacoepidemiologyФАРМАКОЭКОНОМИКА. Современная фармакоэкономика и фармакоэпидемиология2070-49092070-4933IRBIS LLC10.17749/2070-4909/farmakoekonomika.2024.265farmaec-1092Research ArticleORIGINAL ARTICLESОРИГИНАЛЬНЫЕ ПУБЛИКАЦИИDifferential chemoproteomic analysis of RRS-1 candidate molecule and molecules of several nonsteroidal anti-inflammatory drugsДифференциальный хемопротеомный анализ молекулы-кандидата RRS-1 и молекул нескольких нестероидных противовоспалительных препаратовhttps://orcid.org/0000-0003-3190-1437Галенко-ЯрошевскийП. А.Galenko-YaroshevskyP. A.

Галенко-Ярошевский Павел Александрович, д.м.н., проф., чл.-кор. РАН 

ул. Митрофана Седина, д. 4, Краснодар 350063

Pavel A. Galenko-Yaroshevsky, Dr. Sci. Med., Prof., RAS Corr. Member 

4 Mitrofan Sedin Str., Krasnodar 350063

https://orcid.org/0000-0002-2659-7998ТоршинИ. Ю.TorshinI. Yu.

Торшин Иван Юрьевич, к.ф-м.н., к.х.н.

ул. Вавилова, д. 44, корп. 2, Москва 119333

WoS ResearcherID: C-7683-2018. Scopus Author ID: 7003300274

Ivan Yu. Torshin, PhD

44 corp. 2 Vavilov Str., Moscow 119333

WoS ResearcherID: C-7683-2018. Scopus Author ID: 7003300274

https://orcid.org/0000-0001-7507-191XГромовА. Н.GromovA. N.

Громов Андрей Николаевич

ул. Вавилова, д. 44, корп. 2, Москва 119333

WoS ResearcherID: C-7476-2018. Scopus Author ID: 7102053964

Andrey N. Gromov

44 corp. 2 Vavilov Str., Moscow 119333

WoS ResearcherID: C-7476-2018. Scopus Author ID: 7102053964

https://orcid.org/0000-0002-7663-710XГромоваО. А.GromovaO. A.

ромова Ольга Алексеевна, д.м.н., проф. 

ул. Вавилова, д. 44, корп. 2, Москва 119333

WoS ResearcherID: J-4946-2017. Scopus Author ID: 700358981

Olga A. Gromova, Dr. Sci. Med., Prof.

44 corp. 2 Vavilov Str., Moscow 119333

WoS ResearcherID: J-4946-2017. Scopus Author ID: 7003589812

unesco.gromova@gmail.comhttps://orcid.org/0000-0003-4879-0577СуздалевК. Ф.SuzdalevK. F.

Суздалев Константин Филиппович, к.х.н., доцент

ул. Зорге, д. 7, Ростов-на-Дону 344090

Scopus Author ID: 6505813444

Konstantin F. Suzdalev, PhD, Assoc. Prof. 

7 Zorge Str., Rostov-on-Don 344090

Scopus Author ID: 6505813444

https://orcid.org/0000-0001-8873-8461МурашкоР. А.MurashkoR. A.

Мурашко Роман Алексеевич, д.м.н., доцент

ул. Митрофана Седина, д. 4, Краснодар 350063

Roman A. Murashko, Dr. Sci. Med., Assoc. Prof.

4 Mitrofan Sedin Str., Krasnodar 350063

https://orcid.org/0000-0001-9512-2526ЗеленскаяА. В.ZelenskayaA. V.

Зеленская Анаит Владимировна, к.м.н., доцент

ул. Митрофана Седина, д. 4, Краснодар 350063

Anait V. Zelenskaya, PhD, Assoc. Prof. 

4 Mitrofan Sedin Str., Krasnodar 350063

https://orcid.org/0000-0001-9552-8542ЗадорожнийА. В.ZadorozhniyA. V.

Задорожний Андрей Владимирович, к.м.н., доцент

пер. Нахичеванский, д. 29, Ростов-на-Дону 344022

Andrey V. Zadorozhniy, PhD, Assoc. Prof.

29 Nakhichevansky Passage, Rostov-on-Don 344022

https://orcid.org/0009-0002-4983-2433ГлечянТ. Р.GlechyanT. R.

Глечян Тереза Робертовна

ул. Митрофана Седина, д. 4, Краснодар 350063

Tereza R. Glechyan

4 Mitrofan Sedin Str., Krasnodar 350063

https://orcid.org/0009-0001-9511-0370СимавонянГ. В.SimavonyanG. V.

Симавонян Глеб Владимирович

ул. Митрофана Седина, д. 4, Краснодар 350063

4 Mitrofan Sedin Str., Krasnodar 350063

https://orcid.org/0009-0009-2294-7629МухаммадЭ.М. И.MuhammadE.M. I.

Мухаммад Эсан Мохаммад Исхак 

ул. Митрофана Седина, д. 4, Краснодар 350063

Esan M.I. Muhammad

4 Mitrofan Sedin Str., Krasnodar 350063

Федеральное государственное бюджетное образовательное учреждение высшего образования «Кубанский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияKuban State Medical UniversityRussian FederationФедеральный исследовательский центр «Информатика и управление» Российской академии наукРоссияFederal Research Center “Computer Science and Control”, Russian Academy of SciencesRussian FederationФедеральное государственное образовательное учреждение высшего профессионального образования «Южный федеральный университет»РоссияSouthern Federal UniversityRussian FederationФедеральное государственное бюджетное образовательное учреждение высшего образования «Ростовский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияRostov State Medical UniversityRussian Federation202405112024173324336Copyright © Galenko-Yaroshevsky P.A., Torshin I.Y., Gromov A.N., Gromova O.A., Suzdalev K.F., Murashko R.A., Zelenskaya A.V., Zadorozhniy A.V., Glechyan T.R., Simavonyan G.V., Muhammad E.I., 20242024Галенко-Ярошевский П.А., Торшин И.Ю., Громов А.Н., Громова О.А., Суздалев К.Ф., Мурашко Р.А., Зеленская А.В., Задорожний А.В., Глечян Т.Р., Симавонян Г.В., Мухаммад Э.И.Galenko-Yaroshevsky P.A., Torshin I.Y., Gromov A.N., Gromova O.A., Suzdalev K.F., Murashko R.A., Zelenskaya A.V., Zadorozhniy A.V., Glechyan T.R., Simavonyan G.V., Muhammad E.I.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmacoeconomics.ru/jour/article/view/1092Background

Background. To plan effective and safe pharmacotherapy for inflammation and pain, it is important to evaluate the mechanisms and spectrum of action of nonsteroidal anti-inflammatory drugs (NSAIDs), including their effects on human proteome.

Objective

Objective: to identify and evaluate the most significant specific differences of candidate molecule RRS-1 (N-{(Z)-2-(1-methyl-1H-indol-3-yl)1-[(propylamino)carbonyl]vinyl}benzamide) from other NSAIDs through differential chemoreactome analysis.

Material and methods

Material and methods. Chemoproteomic modeling of pharmacological effects of RRS-1 molecule and a number of well-known NSAIDs (diclofenac, nimesulide, ketorolac) on human proteome was carried out on the basis of numerical prediction algorithms over the space of heterogeneous feature descriptions, developed in the topological approach to recognition by Yu.I. Zhuravlev and K.V. Rudakov scientific school.

Results

Results. Significant differences in the effects of the studied molecules were found for 1232 proteins of human proteome. The features of assessing interactions of the studied molecules with 47 target proteins, which most distinguished the effects of RRS-1 molecule from all others were identified. RRS-1 could activate adenosine and dopamine receptors, cannabinoid receptor 2 and GABAA receptor to a greater extent than other molecules. Activation of these receptors corresponded to anti-inflammatory, anti-nociceptive and neuroprotective effects. RRS-1 could preferably inhibit a number of pro-inflammatory proteins, receptor bradykinin 1, metabotropic glutamate receptor 5, matrix metalloproteinases 8, 9, 12, and blood coagulation factor X. Additionally, RRS-1 molecule showed preferable inhibition of a number of kinases targeted in antitumor and anti-inflammatory therapy. RRS-1, less than other studied molecules, interacted with the receptors of vitamin D3, thyroid hormone, acetylcholine, cannabinoids and opioids, orexin, and various metabolic enzymes, which is important in assessment of the safety of using drugs based on this molecule. RRS-1 characteristically exhibited a moderate profile of antivitamin action: the total score of vitamin and mineral loss (7.4±3.7) was significantly less in comparison to diclofenac (11.7±4.5) and was actually on the same level as nimesulide (6.9±3.7) and ketorolac (6.7±3.6).

Conclusion

Conclusion. Chemoreactomic and chemoproteomic profiling of RRS-1 candidate molecule provided pre-experimental assessments of its efficacy and safety through modeling interactions with the human proteome.

Актуальность

Актуальность. Для планирования эффективной и безопасной фармакотерапии воспаления и боли важно оценивать механизмы и спектр действия нестероидных противовоспалительных препаратов (НПВП), включая воздействие на протеом человека.

Цель

Цель: выявить и оценить наиболее существенные отличия молекулы-кандидата RRS-1 (N-{(Z)-2-(1-метил-1H-индол-3-ил)-1-[(пропиламино)карбонил]винил}бензамида) от других НПВП посредством дифференциального хемореактомного анализа.

Материал и методы

Материал и методы. Хемопротеомное моделирование фармакологических эффектов молекулы RRS-1 и ряда известных НПВП (диклофенак, нимесулид, кеторолак) на протеом человека проводилось на основе алгоритмов числового прогнозирования над пространством разнородных признаковых описаний, развиваемых в топологическом подходе к распознаванию научной школы Ю.И. Журавлёва и К.В. Рудакова.

Результаты

Результаты. Достоверные отличия в эффектах исследованных молекул были найдены для 1232 белков протеома человека. Выявлены особенности оценок взаимодействий исследованных молекул с 47 таргетными белками, которые наибольшим образом отличают эффекты молекулы RRS-1 от всех остальных. Соединение RRS-1 может активировать аденозиновые и дофаминовые рецепторы, каннабиноидный рецептор 2 и ГАМКА-рецептор в большей степени, чем другие молекулы (активация этих рецепторов соответствует противовоспалительному, антиноцицептивному и нейропротекторному эффектам). RRS-1 может предпочтительно ингибировать ряд провоспалительных белков, рецептор брадикинина 1, метаботропный глутаматный рецептор 5, матриксные металлопротеиназы 8, 9, 12 и фактор свертывания крови X. Дополнительно показано преимущественное ингибирование молекулой RRS-1 ряда киназ, таргетируемых в противоопухолевой и противовоспалительной терапии. RRS-1 меньше, чем другие исследованные молекулы, взаимодействовал с рецепторами витамина D3, гормона щитовидной железы, ацетилхолина, каннабиноидов и опиоидов, орексина, различных метаболических ферментов, что важно с точки зрения безопасности применения препартов на основе данной молекулы. Вещество RRS-1 отличалось умеренным профилем антивитаминного действия: суммарный балл потери витаминов и минералов (7,4±3,7) был существенно меньше, чем в случае диклофенака (11,7±4,5), и фактически был на одном уровне с нимесулидом (6,9±3,7) и кеторолаком (6,7±3,6).

Заключение

Заключение. Хемореактомное и хемопротеомное профилирование молекулы-кандидата RRS-1 позволило получить доэкспериментальные оценки эффективности и безопасности через моделирование взаимодействий с протеомом человека

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