Chemoreactomic analysis of the drug prototype pilim-1 in comparison with zinc derivatives of nonsteroidal anti-inflammatory drugs

Background. Gastroenterological side effects (esophageal, gastric, and intestinal erosions) associated with the use of drugs from the group of nonsteroidal anti-inflammatory drugs (NSAIDs) highlight the need to explore new molecule candidates with reduced ulcerogenic effects. The zinc-containing molecule candidate pilim-1 has the potential to exhibit anti-inflammatory effects and improve the regenerative properties of the gastric mucosa.

Objective: To explore the anti-inflammatory, ulcerogenic, analgesic, and antivitamin effects of the pilim-1 molecule using chemoreactomic methods.

Material and methods. The chemoreactomic assessment of the pharmacological properties of pilim-1 and zinc derivatives of well-known NSAIDs (ketorolac, diclofenac, and nimesulide) was carried out using the methods of chemoinformatic analysis of molecules developed within the scientific school of Academician Yu.I. Zhuravlev.

Results. Pilim-1 exhibits a distinct anti-inflammatory effect realized through modulation of cytokine activity as well as prostaglandin and leukotriene metabolism. A key distinguishing feature of the pilim-1 molecule is its neutrality with respect to vitamin metabolism while demonstrating a comparable anti-inflammatory potency to zinc-containing NSAID derivatives. The analgesic effect of pilim-1 is based on the inhibition of kinin and histamine receptors. The nociceptin receptor ORL1 can be inhibited by pilim-1 more effectively (IC50 198–214 nM) than zinc-NSAIDs (IC50 361–1093 nM). In the phenylquinone-induced writhing test in rats, pilim-1 demonstrated a slightly higher percentage of analgesia (44%; zinc-NSAIDs: 21–43%). The incidence of gastric ulcers at an oral dose of 100 mg/kg was estimated at 35% (compared to 75% with other molecules). Compared to other zinc-derived NSAID derivatives, pilim-1 exhibits minimal impact on vitamin and mineral metabolism.

Conclusion. Chemoreactomic analysis of pilim-1 indicates promising prospects for its application as an anti-inflammatory drug.

1. Gromova O.A., Torshin I.Iu., Putilina M.V., et al. The chemoreactomic analysis of the central mechanisms of action of non-steroidal anti-inflammatory drugs. S.S. Korsakov Journal of Neurology and Psychiatry. 2020; 120 (1): 70–7 (in Russ.). https://doi.org/10.17116/jnevro202012001170.

2. Galenko-Yaroshevsky P.A., Torshin I.Y., Gromov A.N., et al. Chemoproteomic analysis of the promising candidate molecule of the indole derivative with lab code SV-1010 and other non-steroidal anti-inflammatory drugs. Res Results Pharmacol. 2024; 10 (3): 1–9. https://doi.org/10.18413/rrpharmacology.10.497.

3. Santos L.H., Feres C.A., Melo F.H., et al. Anti-inflammatory, antinociceptive and ulcerogenic activity of a zinc-diclofenac complex in rats. Braz J Med Biol Res. 2004; 37 (8): 1205–13. https://doi.org/10.1590/s0100-879x2004000800011.

4. Sukul A., Poddar S.K., Haque S., et al. Synthesis, characterization and comparison of local analgesic, anti-inflammatory, anti-ulcerogenic activity of copper and zinc complexes of indomethacin. Antiinflamm Antiallergy Agents Med Chem. 2017; 15 (3): 221–33. https://doi.org/10.2174/1871523016666170217103402.

5. Jarosz M., Szkaradek N., Marona H., et al. Evaluation of anti-inflammatory and ulcerogenic potential of zinc-ibuprofen and zinc-naproxen complexes in rats. Inflammopharmacology. 2017; 25 (6): 653–63. https://doi.org/10.1007/s10787-017-0361-0.

6. Gaweł M., Lipkowska A., Herman M., et al. Chronic treatment with zinc hydroaspartate induces anti-inflammatory and anti-ulcerogenic activity in rats. Pharmacol Rep. 2014; 66 (5): 862–6. https://doi.org/10.1016/j.pharep.2014.05.007.

7. Torshin I.Yu. Sensing the change from molecular genetics to personalized medicine. Nova Science Pub Inc; 2012: 366 pp.

8. Torshin I.Y. On solvability, regularity, and locality of the problem of genome annotation. Pattern Recognit Image Anal. 2010; 20: 386–95. https://doi.org/10.1134/S1054661810030156.

9. Torshin I.Yu. On optimization problems arising fromthe application of topological data analysis to the search for forecasting algorithms with fixed correctors. Informatics and Applications. 2023; 17 (2): 2–10 (in Russ.). https://doi.org/10.14357/19922264230201.

10. Torshin I.Yu. On the application of a topological approach to analysis of poorly formalized problems for constructing algorithms for virtual screening of quantum-mechanical properties of organic molecules I: the basics of the problem-oriented theory. Informatics and Applications. 2022; 16 (1): 39–44 (in Russ.). https://doi.org/10.14357/19922264220106.

11. Torshin I.Y., Gromova O.A., Stakhovskaya L.V., Semenov V.A. Chemoreactome analysis of tolperisone, tizanidine, and baclofen molecules: anticholinergic, antispasmodic, and analgesic mechanisms of action. Nevrologiya, neiropsikhiatriya, psikhosomatika / Neurology, Neuropsychiatry, Psychosomatics. 2018; 10 (4): 72–80 (in Russ.). https://doi.org/10.14412/2074-2711-2018-4-72-80.

12. Gromova O.A., Torshin I.Yu. Micronutrients and reproductive health. 2nd ed. Мoscow: GEOTAR-Media; 2022: 832 pp. (in Russ.).

13. Reiterer G., Toborek M., Hennig B. Peroxisome proliferator activated receptors alpha and gamma require zinc for their anti-inflammatory properties in porcine vascular endothelial cells. J Nutr. 2004; 134 (7): 1711–5. https://doi.org/10.1093/jn/134.7.1711.

14. Baumgardner K.R., Sulfaro M.A. The anti-inflammatory effects of human recombinant copper-zinc superoxide dismutase on pulp inflammation. J Endod. 2001; 27 (3): 190–5. https://doi.org/10.1097/00004770-200103000-00014.

15. Gromova O.A., Torshin I.Iu., Pronin A.V., Kilchevsky M.A. Synergistic application of zinc and vitamin C to support memory, attention and the reduction of the risk of the neurological diseases. S.S. Korsakov Journal of Neurology and Psychiatry. 2017; 117 (7): 112–9 (in Russ.). https://doi.org/10.17116/jnevro201711771112-119.

16. Gromova O.A., Torshin I.Yu. The importance of zinc in maintaining the activity of antiviral innate immunity proteins: analysis of publications on COVID-19. The Russian Journal of Preventive Medicine. 2020; 23 (3): 131–9 (in Russ.). https://doi.org/10.17116/profmed202023031131.

17. Prasad A.S. Zinc is an antioxidant and anti-inflammatory agent: its role in human health. Front Nutr. 2014; 1: 14. https://doi.org/10.3389/fnut.2014.00014.

18. Gromova O.A., Torshin I.Yu., Moiseev V.S., et al. The use of zinc and vitamin С for the prevention and adjuvant therapy of acute respiratory diseases. Therapy. 2017; 1 (11): 36–46 (in Russ.).

19. Briassoulis G., Briassoulis P., Ilia S., et al. The anti-oxidative, anti-inflammatory, anti-apoptotic, and anti-necroptotic role of zinc in COVID-19 and sepsis. Antioxidants. 2023; 12 (11): 1942. https://doi.org/10.3390/antiox12111942.

20. Gaweł M., Librowski T., Lipkowska A. Influence of zinc hydroaspartate on the anti-inflammatory and gastric activity of ketoprofen in rats. Pharmacol Rep. 2013; 65 (1): 214–9. https://doi.org/10.1016/s1734-1140(13)70981-2.

21. Hessam S., Sand M., Meier N.M., et al. Combination of oral zinc gluconate and topical triclosan: an anti-inflammatory treatment modality for initial hidradenitis suppurativa. J Dermatol Sci. 2016; 84 (2): 197–202. https://doi.org/10.1016/j.jdermsci.2016.08.010.

22. Chen Y., Cai J., Liu D., et al. Zinc-based metal organic framework with antibacterial and anti-inflammatory properties for promoting wound healing. Regen Biomater. 2022; 9: rbac019. https://doi.org/10.1093/rb/rbac019.

23. Guo J., He L., Li T., et al. Antioxidant and anti-inflammatory effects of different zinc sources on diquat-induced oxidant stress in a piglet model. Biomed Res Int. 2020; 2020: 3464068. https://doi.org/10.1155/2020/3464068.

24. Mei X., Xu D., Xu S., et al. Gastroprotective and antidepressant effects of a new zinc(II)-curcumin complex in rodent models of gastric ulcer and depression induced by stresses. Pharmacol Biochem Behav. 2011; 99 (1): 66–74. https://doi.org/10.1016/j.pbb.2011.04.002.

25. Mei X., Luo X., Xu S., et al. Gastroprotective effects of a new zinc(II)-curcumin complex against pylorus-ligature-induced gastric ulcer in rats. Chem Biol Interact. 2009; 181 (3): 316–21. https://doi.org/10.1016/j.cbi.2009.06.022.

26. Bandyopadhyay B., Bandyopadhyay S.K. Protective effect of zinc gluconate on chemically induced gastric ulcer. Indian J Med Res. 1997; 106: 27–32.

27. Golbabapour S., Gwaram N.S., Hassandarvish P., et al. Gastroprotection studies of Schiff base zinc (II) derivative complex against acute superficial hemorrhagic mucosal lesions in rats. PLoS One. 2013; 8 (9): e75036. https://doi.org/10.1371/journal.pone.0075036.

28. Yu C., Mei X.T., Zheng Y.P., Xu D.H. Gastroprotective effect of taurine zinc solid dispersions against absolute ethanol-induced gastric lesions is mediated by enhancement of antioxidant activity and endogenous PGE2 production and attenuation of NO production. Eur J Pharmacol. 2014; 740: 329–36. https://doi.org/10.1016/j.ejphar.2014.07.014.

29. Rainsford K.D., Whitehouse M.W. Anti-ulcer activity of a slow-release zinc complex, zinc monoglycerolate (Glyzinc). J Pharm Pharmacol. 1992; 44 (6): 476–82. https://doi.org/10.1111/j.2042-7158.1992.tb03650.x.

30. Bulbena O., Escolar G., Navarro C., et al. Gastroprotective effect of zinc acexamate against damage induced by nonsteroidal antiinflammatory drugs. A morphological study. Dig Dis Sci. 1993; 38 (4): 730–9. https://doi.org/10.1007/BF01316807.

31. Donkin J.J., Turner R.J., Hassan I., Vink R. Substance P in traumatic brain injury. Prog Brain Res. 2007; 61: 97–109. https://doi.org/10.1016/S0079-6123(06)61007-8.

32. Galenko-Yaroshevsky P.A., Torshin I.Y., Gromov A.N., et al. Chemoproteomic analysis of the promising candidate molecule of the indole derivative with lab code SV-1010 and other non-steroidal anti-inflammatory drugs. Res Results Pharmacol. 2024; 10 (3): 1–9. https://doi.org/10.18413/rrpharmacology.10.497.

33. Galenko-Yaroshevsky P.A., Torshin I.Yu., Gromov A.N., et al. Differential chemoproteomic analysis of RRS-1 candidate molecule and molecules of several nonsteroidal anti-inflammatory drugs. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2024; 17 (3): 324–36 (in Russ.). https://doi.org/10.17749/2070-4909/farmakoekonomika.2024.265.

34. Galenko-Yaroshevsky P.A., Sergeeva A.V., Torshin I.Yu., et al. Chemoreactome prediction of anti-inflammatory, analgesic, ulcerogenic effects of the candidate molecule N-allylimidazole-zinc in comparison with zinc derivatives of nonsteroidal anti-inflammatory drugs. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2024; 17 (4): 523–34 (in Russ.). https://doi.org/10.17749/2070-4909/farmakoekonomika.2024.279.

35. Galenko-Yaroshevsky P.A., Torshin I.Yu., Gromov A.N., et al. Chemoreactomic analysis of acyzole in comparison with zinc derivatives of nonsteroidal anti-inflammatory drugs. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2024; 17 (1): 48–61 (in Russ.). https://doi.org/10.17749/2070-4909/farmakoekonomika.2024.238.