farmaecFARMAKOEKONOMIKA. Modern Pharmacoeconomics and PharmacoepidemiologyФАРМАКОЭКОНОМИКА. Современная фармакоэкономика и фармакоэпидемиология2070-49092070-4933IRBIS LLC10.17749/2070-4909/farmakoekonomika.2024.214farmaec-961Research ArticleORIGINAL ARTICLESОРИГИНАЛЬНЫЕ ПУБЛИКАЦИИChemoproteomic analysis of the pharmacological properties of vitamin В12 derivativesХемопротеомный анализ фармакологических свойств производных витамина В12https://orcid.org/0000-0002-2659-7998ТоршинИ. Ю.TorshinI. Yu.

Торшин Иван Юрьевич – к.ф-м.н., к.х.н., старший научный сотрудник

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

ул. Вавилова, д. 44, корп. 2, Москва 119334

Ivan Yu. Torshin – PhD (Phys. Math.), PhD (Chem.), Senior Researcher

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

44 corp. 2 Vavilov Str., Moscow 119334

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

Громова Ольга Алексеевна – д.м.н., профессор, ведущий научный сотрудник

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

ул. Вавилова, д. 44, корп. 2, Москва 119334

Olga A. Gromova – Dr. Med. Sc., Professor, Leading Researcher

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

44 corp. 2 Vavilov Str., Moscow 119334

unesco.gromova@gmail.comhttps://orcid.org/0000-0003-1332-4998ДеревеньковИ. А.Dereven’kovI. A.

Деревеньков Илья Александрович – к.х.н., доцент кафедры «Технологии пищевых продуктов и биотехнологии»

WoS ResearcherID: F-2847-2017; Scopus Author ID: 37107505500

пр-т Шереметевский, д. 7, Иваново 153000

Ilia A. Dereven’kov – PhD (Chem.), Associate Professor, Chair of Food Technology and Biotechnology

 WoS ResearcherID: F-2847-2017; Scopus Author ID: 37107505500

7 Sheremetyevsky Ave., Ivanovo 153000

https://orcid.org/0000-0003-1541-9480МайороваЛ. А.MaiorovaL. A.

Майорова Лариса Александровна – д.ф.-м.н., ведущий научный сотрудник

WoS ResearcherID: B-6288-2016; Scopus Author ID: 58079684100

ул. Вавилова, д. 44, корп. 2, Москва 119334

Larissa A. Maiorova – Dr. Phys. Math. Sc., Professor, Leading Researcher

WoS ResearcherID: B-6288-2016; Scopus Author ID: 58079684100

44 corp. 2 Vavilov Str., Moscow 119334

Федеральный исследовательский центр «Информатика и управление» Российской академии наукРоссияFederal Research Center “Computer Science and Control”, Russian Academy of SciencesRussian FederationФедеральное государственное бюджетное образовательное учреждение высшего образования «Ивановский государственный химико-технологический университет»РоссияIvanovo State University of Chemistry and TechnologyRussian Federation202419022024173345357Copyright © Torshin I.Y., Gromova O.A., Dereven’kov I.A., Maiorova L.A., 20242024Торшин И.Ю., Громова О.А., Деревеньков И.А., Майорова Л.А.Torshin I.Y., Gromova O.A., Dereven’kov I.A., Maiorova L.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmacoeconomics.ru/jour/article/view/961Background

Background. Chemical derivatives of vitamin B12 are characterized by a wide range of pharmacological effects. It is important to learn how to establish relationships between changes of the corrin ring structure in vitamin B12 derivatives and changes in pharmacological properties.

Objective

Objective: to evaluate the interaction of six vitamin B12 derivatives (aquacobalamin, diaquacobinamide, aquacyano-forms of heptaethanolamine, heptaethylenediamine, heptamethyl and heptabutyl cobyrinates) with human proteome proteins.

Material and methods

Material and methods. Using the method of chemoinformational (chemoproteomic) analysis, implemented within the framework of algebraic recognition theory and topological data analysis, the constants of half-maximal inhibitory concentration (IC50) and half-maximal effective concentration (EC50) of human proteome proteins were assessed.

Results

Results. Significant differences were found in the interactions of the studied molecules with 1200 proteins. It was shown that the chemoproteomic profiles of each of the compounds form three groups of molecules with similar proteomic properties: (1) aquacobalamin, (2) diaquacobinamide, aquacyano-forms of heptaethanolamine and heptaethylenediamine cobyrinates, (3) aquacyano-forms of heptamethyl and heptabutyl cobyrinates. A more detailed analysis of the chemoproteomic profiles of the studied compounds using the GO (Gene Ontology) nomenclature of biological functions of proteins made it possible to identify functional GO categories indicating differences in the biological effects of the studied compounds: neuroprotective regulation of neurotransmitter activity (serotonin receptor activity, cholinergic synapses, regulation of dopamine secretion, receptor thyroid hormones), reduction of inflammation (inhibition of cytokine biosynthesis, including tumor necrosis factor alpha and interleukin 1 beta, I-kappa-B kinases / nuclear factor kappa В, leukocyte migration), etc.

Conclusion

Conclusion. The profiles of differences in the pharmacological properties of the studied compounds with respect to their effects on neuroprotection, neurotransmitter metabolism, and inflammation were identified and described.

Актуальность

Актуальность. Химические производные витамина В12 характеризуются широким спектром фармакологического действия. Важно научиться устанавливать взаимосвязи между изменениями структуры корринового кольца в производных витамина В12 и изменениями фармакологических свойств.

Цель

Цель: оценка взаимодействия шести производных витамина В12 (аквакобаламин, диаквакобинамид, аквациано-формы гептаэтаноламин-, гептаэтилендиамин-, гептаметил- и гептабутилкобиринатов) с белками протеома человека.

Материал и методы

Материал и методы. Методом хемоинформационного (хемопротеомного) анализа, реализованного в рамках алгебраической теории распознавания и топологического анализа данных, проведены оценки констант концентрации полумаксимального ингибирования (англ. half-maximal inhibitory concentration, IC50) и полумаксимальной эффективной концентрации (англ. half-maximal effective concentration, ЕС50) белков протеома человека.

Результаты

Результаты. Найдены достоверные отличия во взаимодействиях исследованных молекул с 1200 белками. Показано, что хемопротеомные профили каждого из соединений формируют три группы молекул с близкими протеомными свойствами: 1) аквакобаламин; 2) диаквакобинамид, аквациано-формы гептаэтаноламин- и гептаэтилендиаминкобиринатов; 3) аквациано-формы гептаметил- и гептабутилкобиринатов. Более детальный анализ хемопротеомных профилей исследуемых соединений с использованием номенклатуры биологических функций белков GO (англ. Gene Ontology) позволил выделить функциональные категории GO, указывающие на различия в биологических эффектах исследуемых соединений: нейропротективная регуляция активности нейротрансмиттеров (активность рецептора серотонина, холинергические синапсы, регуляция секреции дофамина, рецептор гормонов щитовидной железы), снижение воспаления (ингибирование биосинтеза цитокинов, в т.ч. фактора некроза опухоли альфа и интерлейкина 1-бета, I-каппа-B киназы / ядерного фактора каппа-B, миграции лейкоцитов) и др.

Заключение

Заключение. Выявлены и описаны профили отличий фармакологических свойств исследуемых соединений относительно воздействия на нейропротекцию, обмен нейротрансмиттеров и воспаление.

Синтетические производные витамина В12хемопротеомный анализтопологическая теория анализа данныхоценка фармакологических свойствпротеом человекаSynthetic derivatives of vitamin B12chemoproteomic analysistopological theory of data analysisassessment of pharmacological propertieshuman proteomeРабота выполнена при поддержке гранта Российского научного фонда № 20-12-00175-п на базе ФГБОУ ВО «Ивановский государственный химико-технологический университет»The work was supported by the grant of the Russian Science Foundation No. 20-12-00175-p on the base of Ivanovo State University of Chemistry and Technology.ReferencesГромова О.А., Торшин И.Ю., Гусев Е.И. Синергидные нейропротекторные эффекты тиамина, пиридоксина и цианокобаламина в рамках протеома человека. Фармакокинетика и фармакодинамика. 2017; 1: 40–51.Gromova O.A., Torshin I.Yu., Gusev E.I. Synergistic neuroprotective effects of thiamine, pyridoxine and cyanocobalamin on the level of human proteome. Pharmacokinetics and Pharmacodynamics. 2017; 1: 40–51 (in Russ.).Торшин И.Ю., Громова О.А., Майорова Л.А. О перспективах применения производных витамина В12 в фармакологии. ФАРМАКОЭКОНОМИКА. Современная фармакоэкономика и фармакоэпидемиология. 2023; 16 (3): 501–11. https://doi.org/10.17749/2070-4909/farmakoekonomika.2023.198.Torshin I.Yu., Gromova O.A., Maiorova L.A. The рrospects for the use of vitamin В12 derivatives in pharmacology. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2023; 16 (3): 501–11 (in Russ.). https://doi.org/10.17749/2070-4909/farmakoekonomika.2023.198.Карлюк М.В., Крыгин Ю.Ю., Майорова-Валькова Л.А. и др. Формирование двумерных (M) и трехмерных (V) наноагрегатов замещенного порфирина кобальта в ленгмюровских слоях и пленках Ленгмюра–Шефера. Известия Академии наук. Серия химическая. 2013; 62 (2): 471–9 (на англ. яз). https://doi.org/10.1007/s11172-013-0066-5.Karlyuk M.V., Krygin Y.Y., Maiorova-Valkova L.A., et al. Formation of two-dimensional (M) and three-dimensional (V) nanoaggregates of substituted cobalt porphyrin in the Langmuir layers and Langmuir–Schaefer films. Russian Chemical Bulletin. 2013; 62 (2): 471–9. https://doi.org/10.1007/s11172-013-0066-5.Петровa M.В., Майоровa Л.А., Громова O.A. и др. Наноструктура ленгмюровских М-монослоев тетрафенилпорфирината цинка(II), сформированных с использованием раствора низкой концентрации. Макрогетероциклы. 2014; 7 (3): 267–71 (на англ. яз.). https://doi.org/10.6060/mhc131163m.Petrova M.V., Maiorova L.A., Gromova O.A., et al. Nanostructure of Zinc(II) tetraphenylporphyrinate Langmuir M-monolayers formed with diluted solution. Macroheterocycles. 2014; 7 (3): 267–71. https://doi.org/10.6060/mhc131163m.Maiorova L.A., Vu T.T., Gromova O.A., et al. Nanostructured stable floating М-mono- and bilayers and Langmuir–Schaefer films of 5,10,15-triphenylcorrole. BioNanoSci. 2018; 8 (1): 81–9. https://doi.org/10.1007/s12668-017-0424-0.Maiorova L.A., Vu T.T., Gromova O.A., et al. Nanostructured stable floating М-mono- and bilayers and Langmuir–Schaefer films of 5,10,15-triphenylcorrole. BioNanoSci. 2018; 8 (1): 81–9. https://doi.org/10.1007/s12668-017-0424-0.Stupperich E., Nexø E.. Effect of the cobalt-N coordination on the cobamide recognition by the human vitamin B12 binding proteins intrinsic factor, transcobalamin and haptocorrin. Eur J Biochem. 1991; 199 (2): 299–303. https://doi.org/10.1111/j.1432-1033.1991.tb16124.x.Stupperich E., Nexø E.. Effect of the cobalt-N coordination on the cobamide recognition by the human vitamin B12 binding proteins intrinsic factor, transcobalamin and haptocorrin. Eur J Biochem. 1991; 199 (2): 299–303. https://doi.org/10.1111/j.1432-1033.1991.tb16124.x.Dereven’kov I.A., Hannibal L., Makarov S.V., et al. Characterization of the complex between native and reduced bovine serum albumin with aquacobalamin and evidence of dual tetrapyrrole binding. J Biol Inorg Chem. 2018; 23 (5): 725–38. https://doi.org/10.1007/s00775-018-1562-8.Dereven’kov I.A., Hannibal L., Makarov S.V., et al. Characterization of the complex between native and reduced bovine serum albumin with aquacobalamin and evidence of dual tetrapyrrole binding. J Biol Inorg Chem. 2018; 23 (5): 725–38. https://doi.org/10.1007/s00775-018-1562-8.Деревеньков И.А., Макаров С.В., Молодцов П.А. Влияние бычьего сывороточного альбумина на редокс реакции и лигандный обмен с участием аквакобаламина. Макрогетероциклы. 2020; 13 (3): 223–8 (на англ. яз). https://doi.org/10.6060/mhc200498d.Dereven’kov I.A., Makarov S.V., Molodtsov P.A. Effect of bovine serum albumin on redox and ligand exchange reactions involving aquacobalamin. Macroheterocycles. 2020; 13 (3): 223–8. https://doi.org/10.6060/mhc200498d.Dereven’kov I.A., Osokin V.S., Molodtsov P.A., et al. Effect of complexation between cobinamides and bovine serum albumin on their reactivity toward cyanide. React Kinet Mech Cat. 2022; 135 (3): 1469–83. https://doi.org/10.1007/s11144-022-02216-8.Dereven’kov I.A., Osokin V.S., Molodtsov P.A., et al. Effect of complexation between cobinamides and bovine serum albumin on their reactivity toward cyanide. React Kinet Mech Cat. 2022; 135 (3): 1469–83. https://doi.org/10.1007/s11144-022-02216-8.Dereven’kov I.A., Dzvinkas I.I., Osokin V.S., Makarov S.V. Effect of bovine serum albumin on the water solubility of hydrophobic corrinoids. J Porphyrins Phthalocyanines. 2023; 27 (5): 811–7. https://doi.org/10.1142/S1088424623500633.Dereven’kov I.A., Dzvinkas I.I., Osokin V.S., Makarov S.V. Effect of bovine serum albumin on the water solubility of hydrophobic corrinoids. J Porphyrins Phthalocyanines. 2023; 27 (5): 811–7. https://doi.org/10.1142/S1088424623500633.Gromova O.A., Torshin I.Yu., Maiorova L.A., et al. Bioinformatic and chemoneurocytological analysis of the pharmacological properties of vitamin B12 and some of its derivatives. J Porphyrins Phthalocyanines. 2021; 25 (9): 835–42. https://doi.org/10.1142/S1088424621500644.Gromova O.A., Torshin I.Yu., Maiorova L.A., et al. Bioinformatic and chemoneurocytological analysis of the pharmacological properties of vitamin B12 and some of its derivatives. J Porphyrins Phthalocyanines. 2021; 25 (9): 835–42. https://doi.org/10.1142/S1088424621500644.Gromova O.A., Maiorova L.A., Salnikov D.S., et al. Vitamin B12 hydrophobic derivative exhibits bioactivity: biomedical and photophysical study. BioNanoSci. 2022; 12 (7): 74–82. https://doi.org/10.1007/s12668-021-00916-4.Gromova O.A., Maiorova L.A., Salnikov D.S., et al. Vitamin B12 hydrophobic derivative exhibits bioactivity: biomedical and photophysical study. BioNanoSci. 2022; 12 (7): 74–82. https://doi.org/10.1007/s12668-021-00916-4.Valkova L.A., Glibin A.S., Valli L. Quantitative analysis of compression isotherms of fullerene C60 Langmuir layers. Colloid J. 2008; 70: 6–11. https://doi.org/10.1134/S1061933X0801002X.Valkova L.A., Glibin A.S., Valli L. Quantitative analysis of compression isotherms of fullerene C60 Langmuir layers. Colloid J. 2008; 70: 6–11. https://doi.org/10.1134/S1061933X0801002X.Valkova L.A., Glibin A.S., Koifman O.I. Influence of the solvent nature on the structure of two-dimensional nanoaggregates in Langmuir layers of copper tetra-tert-butyltetrabenzotriazaporphyrin. Macroheterocycles. 2011; 4 (3): 222–6.Valkova L.A., Glibin A.S., Koifman O.I. Influence of the solvent nature on the structure of two-dimensional nanoaggregates in Langmuir layers of copper tetra-tert-butyltetrabenzotriazaporphyrin. Macroheterocycles. 2011; 4 (3): 222–6.Erokhin V., Carrara S., Paternolli C., et al. X-ray study of structural reorganization in phthalocyanine containing Langmuir–Blodgett heterostructures. Appl Surf Sci. 2005; 245 (1): 369–75. https://doi.org/10.1016/j.apsusc.2004.10.047.Erokhin V., Carrara S., Paternolli C., et al. X-ray study of structural reorganization in phthalocyanine containing Langmuir–Blodgett heterostructures. Appl Surf Sci. 2005; 245 (1): 369–75. https://doi.org/10.1016/j.apsusc.2004.10.047.Valkova L.A., Erokhin V.V., Glibin A.S., Koifman O.I. The influence of molecular structure and π-system extent on nano- and microstructure of Langmuir layers of copper azaporphyrins. J Porphyr Phthalocyanines. 2011; 15 (09n10): 1044–51. https://doi.org/10.1142/S1088424611004026.Valkova L.A., Erokhin V.V., Glibin A.S., Koifman O.I. The influence of molecular structure and π-system extent on nano- and microstructure of Langmuir layers of copper azaporphyrins. J Porphyr Phthalocyanines. 2011; 15 (09n10): 1044–51. https://doi.org/10.1142/S1088424611004026.Valkova L.A., Shabyshev L.S., Feigin L.A., Akopova O.B. Formation and X-ray diffraction investigation of Langmuir–Blodgett films of liquid crystalline substituted crown esters. Mol Cryst Liquid Cryst. 1996; 6 (4): 291–8.Valkova L.A., Shabyshev L.S., Feigin L.A., Akopova O.B. Formation and X-ray diffraction investigation of Langmuir–Blodgett films of liquid crystalline substituted crown esters. Mol Cryst Liquid Cryst. 1996; 6 (4): 291–8.Valkova L., Borovkov N., Maccioni E., et al. Influence of molecular and supramolecular factors on sensor properties of Langmuir–Blodgett films of tert-butyl-substituted copper azaporphyrines towards hydrocarbons. Coll Surf Physicochem Eng Aspects. 2002; 198–200: 891–6. https://doi.org/10.1016/S0927-7757(01)01016-0.Valkova L., Borovkov N., Maccioni E., et al. Influence of molecular and supramolecular factors on sensor properties of Langmuir–Blodgett films of tert-butyl-substituted copper azaporphyrines towards hydrocarbons. Coll Surf Physicochem Eng Aspects. 2002; 198–200: 891–6. https://doi.org/10.1016/S0927-7757(01)01016-0.Valkova L.A., Betrencourt C., Hochapfel A., et al. Monolayer study of monensin and lasalocid in the gas state. Mol Cryst Liquid Cryst. 1996; 287: 269–73. https://doi.org/10.1080/10587259608038763.Valkova L.A., Betrencourt C., Hochapfel A., et al. Monolayer study of monensin and lasalocid in the gas state. Mol Cryst Liquid Cryst. 1996; 287: 269–73. https://doi.org/10.1080/10587259608038763.Maiorova L.A., Kobayashi N., Salnikov D.S., et al. Supermolecular nanoentities of vitamin B12 derivative as a link in the evolution of the parent molecules during self-assembly at the air-water interface. Langmuir. 2023; 39 (9): 3246–54. https://doi.org/10.1021/acs.langmuir.2c02964.Maiorova L.A., Kobayashi N., Salnikov D.S., et al. Supermolecular nanoentities of vitamin B12 derivative as a link in the evolution of the parent molecules during self-assembly at the air-water interface. Langmuir. 2023; 39 (9): 3246–54. https://doi.org/10.1021/acs.langmuir.2c02964.Torshin I.Yu., Rudakov K.V. On the procedures of generation of numerical features over partitions of sets of objects in the problem of predicting numerical target variables. Pattern Recogni Image Anal. 2019; 29 (4): 654–67. https://doi.org/10.1134/S1054661819040175.Torshin I.Yu., Rudakov K.V. On the procedures of generation of numerical features over partitions of sets of objects in the problem of predicting numerical target variables. Pattern Recogni Image Anal. 2019; 29 (4): 654–67. https://doi.org/10.1134/S1054661819040175.Torshin I.Yu. The study of the solvability of the genome annotation problem on sets of elementary motifs. Pattern Recognit Image Anal. 2011; 21 (4): 652–62. https://doi.org/10.1134/S1054661811040171.Torshin I.Yu. The study of the solvability of the genome annotation problem on sets of elementary motifs. Pattern Recognit Image Anal. 2011; 21 (4): 652–62. https://doi.org/10.1134/S1054661811040171.Torshin I.Yu., Rudakov K.V. On the application of the combinatorial theory of solvability to the analysis of chemographs. Part 1: Fundamentals of modern chemical bonding theory and the concept of the chemograph. Pattern Recognit Image Anal. 2014; 24 (1): 11–23. https://doi.org/10.1134/S1054661814010209.Torshin I.Yu., Rudakov K.V. On the application of the combinatorial theory of solvability to the analysis of chemographs. Part 1: Fundamentals of modern chemical bonding theory and the concept of the chemograph. Pattern Recognit Image Anal. 2014; 24 (1): 11–23. https://doi.org/10.1134/S1054661814010209.Torshin I.Yu., Rudakov K.V. On the application of the combinatorial theory of solvability to the analysis of chemographs. Part 2: Local completeness of invariants of chemographs in view of the combinatorial theory of solvability. Pattern Recognit Image Anal. 2014; 24 (2): 196–208. https://doi.org/10.1134/S1054661814020151.Torshin I.Yu., Rudakov K.V. On the application of the combinatorial theory of solvability to the analysis of chemographs. Part 2: Local completeness of invariants of chemographs in view of the combinatorial theory of solvability. Pattern Recognit Image Anal. 2014; 24 (2): 196–208. https://doi.org/10.1134/S1054661814020151.Рудаков К.В., Торшин И.Ю. Об отборе информативных значений признаков на базе критериев разрешимости в задаче распознавания вторичной структуры белка. Доклады Aкадемии наук. 2011; 441 (1): 24–8.Rudakov K.V., Torshin I.Yu. On the selection of informative values of features based on solvability criteria in the task of recognizing the secondary structure of protein. Doklady Akademii nauk / Reports of the Academy of Sciences. 2011; 441 (1): 24–8 (in Russ.).Torshin I.Yu., Rudakov K.V. Topological chemograph analysis theory as a promising approach to simulation modeling of quantum-mechanical properties of molecules. Part II: Quantum-chemical interpretations of chemograph theory. Pattern Recognit Image Anal. 2021; 31 (4): 884–96. https://doi.org/10.1134/S1054661821040258.Torshin I.Yu., Rudakov K.V. Topological chemograph analysis theory as a promising approach to simulation modeling of quantum-mechanical properties of molecules. Part II: Quantum-chemical interpretations of chemograph theory. Pattern Recognit Image Anal. 2021; 31 (4): 884–96. https://doi.org/10.1134/S1054661821040258.Bolton E., Wang Y., Thiessen P.A., Bryant S.H. Chapter 12 – PubChem: Integrated Platform of Small Molecules and Biological Activities. Ann Rep Comput Chem. 2008; 4: 217–41. https://doi.org/10.1016/S1574-1400(08)00012-1.Bolton E., Wang Y., Thiessen P.A., Bryant S.H. Chapter 12 – PubChem: Integrated Platform of Small Molecules and Biological Activities. Ann Rep Comput Chem. 2008; 4: 217–41. https://doi.org/10.1016/S1574-1400(08)00012-1.Reading S.A., Barclay J.K. A1 receptor activation decreases fatigue in mammalian slow-twitch skeletal muscle in vitro. Can J Physiol Pharmacol. 2001; 79 (6): 496–501.Reading S.A., Barclay J.K. A1 receptor activation decreases fatigue in mammalian slow-twitch skeletal muscle in vitro. Can J Physiol Pharmacol. 2001; 79 (6): 496–501.Chini C.C., Escande C., Nin V., Chini E.N. DBC1 (Deleted in Breast Cancer 1) modulates the stability and function of the nuclear receptor Rev-erbα. Biochem J. 2013; 451 (Pt. 3): 453–61. https://doi.org/10.1042/BJ20121085.Chini C.C., Escande C., Nin V., Chini E.N. DBC1 (Deleted in Breast Cancer 1) modulates the stability and function of the nuclear receptor Rev-erbα. Biochem J. 2013; 451 (Pt. 3): 453–61. https://doi.org/10.1042/BJ20121085.Klatt K.C., Petviashvili E.J., Moore D.D. LRH-1 induces hepatoprotective nonessential amino acids in response to acute liver injury. J Clin Invest. 2023; 133 (7): e168805. https://doi.org/10.1172/JCI168805.Klatt K.C., Petviashvili E.J., Moore D.D. LRH-1 induces hepatoprotective nonessential amino acids in response to acute liver injury. J Clin Invest. 2023; 133 (7): e168805. https://doi.org/10.1172/JCI168805.Yan Y., Jiang W., Spinetti T., et al. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity. 2013; 38 (6): 1154–63. https://doi.org/10.1016/j.immuni.2013.05.015.Yan Y., Jiang W., Spinetti T., et al. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity. 2013; 38 (6): 1154–63. https://doi.org/10.1016/j.immuni.2013.05.015.Miller D.J., Adams S.E., Hallett M.B., Allemann R.K. Calpain-1 inhibitors for selective treatment of rheumatoid arthritis: what is the future? Future Med Chem. 2013; 5 (17): 2057–74. https://doi.org/10.4155/fmc.13.172.Miller D.J., Adams S.E., Hallett M.B., Allemann R.K. Calpain-1 inhibitors for selective treatment of rheumatoid arthritis: what is the future? Future Med Chem. 2013; 5 (17): 2057–74. https://doi.org/10.4155/fmc.13.172.Fà M., Zhang H., Staniszewski A., et al. Novel selective calpain 1 inhibitors as potential therapeutics in Alzheimer's disease. J Alzheimers Dis. 2016; 49 (3): 707–21. https://doi.org/10.3233/JAD-150618.Fà M., Zhang H., Staniszewski A., et al. Novel selective calpain 1 inhibitors as potential therapeutics in Alzheimer's disease. J Alzheimers Dis. 2016; 49 (3): 707–21. https://doi.org/10.3233/JAD-150618.Hurtado-Alvarado G., Domínguez-Salazar E., Velázquez-Moctezuma J., Gómez-González B. A2A adenosine receptor antagonism reverts the blood-brain barrier dysfunction induced by sleep restriction. PLoS One. 2016; 11 (11): e0167236. https://doi.org/10.1371/journal.pone.0167236.Hurtado-Alvarado G., Domínguez-Salazar E., Velázquez-Moctezuma J., Gómez-González B. A2A adenosine receptor antagonism reverts the blood-brain barrier dysfunction induced by sleep restriction. PLoS One. 2016; 11 (11): e0167236. https://doi.org/10.1371/journal.pone.0167236.Fraering P.C., Ye W., Strub J.M., et al. Purification and characterization of the human gamma-secretase complex. Biochemistry. 2004; 43 (30): 9774–89. https://doi.org/10.1021/bi0494976.Fraering P.C., Ye W., Strub J.M., et al. Purification and characterization of the human gamma-secretase complex. Biochemistry. 2004; 43 (30): 9774–89. https://doi.org/10.1021/bi0494976.Marambaud P., Shioi J., Serban G., et al. A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 2002; 21 (8): 1948–56. https://doi.org/10.1093/emboj/21.8.1948.Marambaud P., Shioi J., Serban G., et al. A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 2002; 21 (8): 1948–56. https://doi.org/10.1093/emboj/21.8.1948.Asuni A.A., Hooper C., Reynolds C.H., et al. GSK3alpha exhibits beta-catenin and tau directed kinase activities that are modulated by Wnt. Eur J Neurosci. 2006; 24 (12): 3387–92. https://doi.org/10.1111/j.1460-9568.2006.05243.x.Asuni A.A., Hooper C., Reynolds C.H., et al. GSK3alpha exhibits beta-catenin and tau directed kinase activities that are modulated by Wnt. Eur J Neurosci. 2006; 24 (12): 3387–92. https://doi.org/10.1111/j.1460-9568.2006.05243.x.Wong A.S., Lee R.H., Cheung A.Y., et al. Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson's disease. Nat Cell Biol. 2011; 13 (5): 568–79. https://doi.org/10.1038/ncb2217.Wong A.S., Lee R.H., Cheung A.Y., et al. Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson's disease. Nat Cell Biol. 2011; 13 (5): 568–79. https://doi.org/10.1038/ncb2217.Ozcan L., Kasikara C., Yurdagul A. Jr., et al. Allosteric MAPKAPK2 inhibitors improve plaque stability in advanced atherosclerosis. PLoS One. 2021; 16 (5): e0246600. https://doi.org/10.1371/journal.pone.0246600.Ozcan L., Kasikara C., Yurdagul A. Jr., et al. Allosteric MAPKAPK2 inhibitors improve plaque stability in advanced atherosclerosis. PLoS One. 2021; 16 (5): e0246600. https://doi.org/10.1371/journal.pone.0246600.Triantafilou K., Triantafilou M., Dedrick R.L. A CD14-independent LPS receptor cluster. Nat Immunol. 2001; 2 (4): 338–45. https://doi.org/10.1038/86342.Triantafilou K., Triantafilou M., Dedrick R.L. A CD14-independent LPS receptor cluster. Nat Immunol. 2001; 2 (4): 338–45. https://doi.org/10.1038/86342.Hoarau C., Gérard B., Lescanne E., et al. TLR9 activation induces normal neutrophil responses in a child with IRAK-4 deficiency: involvement of the direct PI3K pathway. J Immunol. 2007; 179 (7): 4754–65. https://doi.org/10.4049/jimmunol.179.7.4754.Hoarau C., Gérard B., Lescanne E., et al. TLR9 activation induces normal neutrophil responses in a child with IRAK-4 deficiency: involvement of the direct PI3K pathway. J Immunol. 2007; 179 (7): 4754–65. https://doi.org/10.4049/jimmunol.179.7.4754.Gilchrist A., Echeverria S.L. Targeting chemokine receptor CCR1 as a potential therapeutic approach for multiple myeloma. Front Endocrinol. 2022; 13: 846310. https://doi.org/10.3389/fendo.2022.846310.Gilchrist A., Echeverria S.L. Targeting chemokine receptor CCR1 as a potential therapeutic approach for multiple myeloma. Front Endocrinol. 2022; 13: 846310. https://doi.org/10.3389/fendo.2022.846310.Wu Y., Xi J., Li Y., et al. Discovery of a potent and selective CCR8 small molecular antagonist IPG7236 for the treatment of cancer. J Med Chem. 2023; 66 (7): 4548–64. https://doi.org/10.1021/acs.jmedchem.3c00030.Wu Y., Xi J., Li Y., et al. Discovery of a potent and selective CCR8 small molecular antagonist IPG7236 for the treatment of cancer. J Med Chem. 2023; 66 (7): 4548–64. https://doi.org/10.1021/acs.jmedchem.3c00030.Willems L.I., Ijzerman A.P. Small molecule antagonists for chemokine CCR3 receptors. Med Res Rev. 2010; 30 (5): 778–817. https://doi.org/10.1002/med.20181.Willems L.I., Ijzerman A.P. Small molecule antagonists for chemokine CCR3 receptors. Med Res Rev. 2010; 30 (5): 778–817. https://doi.org/10.1002/med.20181.Kim S.F., Huri D.A, Snyder S.H. Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science. 2005; 310 (5756): 1966–70. https://doi.org/10.1126/science.1119407.Kim S.F., Huri D.A, Snyder S.H. Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science. 2005; 310 (5756): 1966–70. https://doi.org/10.1126/science.1119407.Makridakis N.M., di Salle E., Reichardt J.K. Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II. Pharmacogenetics. 2000; 10 (5): 407–13. https://doi.org/10.1097/00008571-200007000-00004.Makridakis N.M., di Salle E., Reichardt J.K. Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II. Pharmacogenetics. 2000; 10 (5): 407–13. https://doi.org/10.1097/00008571-200007000-00004.Haeggström J.Z., Wetterholm A., Shapiro R., et al. Leukotriene A4 hydrolase: a zinc metalloenzyme. Biochem Biophys Res Commun. 1990; 172 (3): 965–70. https://doi.org/10.1016/0006-291x(90)91540-9.Haeggström J.Z., Wetterholm A., Shapiro R., et al. Leukotriene A4 hydrolase: a zinc metalloenzyme. Biochem Biophys Res Commun. 1990; 172 (3): 965–70. https://doi.org/10.1016/0006-291x(90)91540-9.Oberlies J., Watzl C., Giese T., et al. Regulation of NK cell function by human granulocyte arginase. J Immunol. 2009; 182 (9): 5259–67. https://doi.org/10.4049/jimmunol.0803523.Oberlies J., Watzl C., Giese T., et al. Regulation of NK cell function by human granulocyte arginase. J Immunol. 2009; 182 (9): 5259–67. https://doi.org/10.4049/jimmunol.0803523.Ostermann G., Weber K.S., Zernecke A., et al. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol. 2002; 3 (2): 151–8. https://doi.org/10.1038/ni755.Ostermann G., Weber K.S., Zernecke A., et al. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol. 2002; 3 (2): 151–8. https://doi.org/10.1038/ni755.Kim T., Jeon J., Park J.S., et al. Matrix metalloproteinase-8 inhibitor ameliorates inflammatory responses and behavioral deficits in LRRK2 G2019S Parkinson's disease model mice. Biomol Ther. 2021; 29 (5): 483–91. https://doi.org/10.4062/biomolther.2020.181.Kim T., Jeon J., Park J.S., et al. Matrix metalloproteinase-8 inhibitor ameliorates inflammatory responses and behavioral deficits in LRRK2 G2019S Parkinson's disease model mice. Biomol Ther. 2021; 29 (5): 483–91. https://doi.org/10.4062/biomolther.2020.181.Jakimiuk K., Gesek J., Atanasov A.G., Tomczyk M. Flavonoids as inhibitors of human neutrophil elastase. J Enzyme Inhib Med Chem. 2021; 36 (1): 1016–28. https://doi.org/10.1080/14756366.2021.1927006.Jakimiuk K., Gesek J., Atanasov A.G., Tomczyk M. Flavonoids as inhibitors of human neutrophil elastase. J Enzyme Inhib Med Chem. 2021; 36 (1): 1016–28. https://doi.org/10.1080/14756366.2021.1927006.Kunz D., Gerard N.P., Gerard C. The human leukocyte platelet-activating factor receptor. cDNA cloning, cell surface expression, and construction of a novel epitope-bearing analog. J Biol Chem. 1992; 267 (13): 9101–6.Kunz D., Gerard N.P., Gerard C. The human leukocyte platelet-activating factor receptor. cDNA cloning, cell surface expression, and construction of a novel epitope-bearing analog. J Biol Chem. 1992; 267 (13): 9101–6.Mao S.S., Cooper C.M., Wood T., et al. Characterization of plasmin-mediated activation of plasma procarboxypeptidase B. Modulation by glycosaminoglycans. J Biol Chem. 1999; 274 (49): 35046–52. https://doi.org/10.1074/jbc.274.49.35046.Mao S.S., Cooper C.M., Wood T., et al. Characterization of plasmin-mediated activation of plasma procarboxypeptidase B. Modulation by glycosaminoglycans. J Biol Chem. 1999; 274 (49): 35046–52. https://doi.org/10.1074/jbc.274.49.35046.Wang S., Beck R., Blench T., et al. Studies of benzothiophene template as potent factor IXa (FIXa) inhibitors in thrombosis. J Med Chem. 2010; 53 (4): 1465–72. https://doi.org/10.1021/jm901475e.Wang S., Beck R., Blench T., et al. Studies of benzothiophene template as potent factor IXa (FIXa) inhibitors in thrombosis. J Med Chem. 2010; 53 (4): 1465–72. https://doi.org/10.1021/jm901475e.

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