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image of Exploration of Resveratrol Derivatives as Novel Therapeutic Modulators of 11β-Hydroxysteroid Dehydrogenase 1 Activity in Metabolic Dysregulation

Abstract

Background

Metabolic dysregulation, encompassing conditions such as type 2 diabetes mellitus, obesity, metabolic syndrome, and dyslipidemia, poses an increasing global health burden. The dysregulation of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a key enzyme in glucocorticoid metabolism, has been strongly implicated in the pathogenesis of these disorders by influencing glucose homeostasis, lipid metabolism, and insulin sensitivity. Consequently, targeting 11β-HSD1 offers a promising therapeutic strategy for mitigating metabolic dysregulation and its associated complications.

Aim

The study aimed to identify resveratrol derivatives with high binding affinity and inhibitory potential against 11β-HSD1, using computational approaches to evaluate their pharmacokinetic and toxicity profiles.

Methods

A library of resveratrol derivatives was screened using molecular docking to identify high-affinity compounds. The hit compounds were further evaluated for absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, followed by molecular dynamics simulations to assess their stability.

Results

The resveratrol cis-dehydrodimer emerged as the most promising candidate, demonstrating high binding affinity, favorable ADMET properties, and stability over a 200 ns simulation period. These findings suggest its potential as a small-molecule inhibitor of 11β-HSD1.

Conclusion

The resveratrol cis-dehydrodimer represents a viable candidate for further experimental validation as a therapeutic agent for metabolic disorders. Future studies should include synthetic validation and testing to confirm its efficacy.

© 2025 Bentham Science Publishers
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2025-07-30
2025-11-04

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References

  1. Li W. Chen D. Peng Y. Lu Z. Kwan M.P. Tse L.A. Association between metabolic syndrome and mortality: Prospective cohort study. JMIR Public Health Surveill. 2023 9 e44073 10.2196/44073 37669100
    [Google Scholar]
  2. Sharma A. Vella A. Glucose metabolism in Cushing’s syndrome. Curr. Opin. Endocrinol. Diabetes Obes. 2020 27 3 140 145 10.1097/MED.0000000000000537 32250974
    [Google Scholar]
  3. Janssen J.A.M.J.L. New insights into the role of insulin and hypothalamic-pituitary-adrenal (HPA) axis in the metabolic syndrome. Int. J. Mol. Sci. 2022 23 15 8178 10.3390/ijms23158178 35897752
    [Google Scholar]
  4. Kupczyk D. Bilski R. Kozakiewicz M. Studzińska R. Kędziora-Kornatowska K. Kosmalski T. Pedrycz-Wieczorska A. Głowacka M. 11β-HSD as a new target in pharmacotherapy of metabolic diseases. Int. J. Mol. Sci. 2022 23 16 8984 10.3390/ijms23168984 36012251
    [Google Scholar]
  5. Kupczyk D. Studzińska R. Kołodziejska R. Baumgart S. Modrzejewska M. Woźniak A. 11β-hydroxysteroid dehydrogenase type 1 as a potential treatment target in cardiovascular diseases. J. Clin. Med. 2022 11 20 6190 10.3390/jcm11206190 36294507
    [Google Scholar]
  6. Aziz H Raslan M El Dahshan D Afify M Hamimy W Gouda W. 11β Hydroxysteroid dehydrogenase type 1 gene expression in obesity and its complications. Egypt J Chem 2022 66 7 165 174 10.21608/ejchem.2022.157145.6819
    [Google Scholar]
  7. Li J.X. Cummins C.L. Fresh insights into glucocorticoid-induced diabetes mellitus and new therapeutic directions. Nat. Rev. Endocrinol. 2022 18 9 540 557 10.1038/s41574‑022‑00683‑6 35585199
    [Google Scholar]
  8. Devang N. M N. Rao S. Adhikari P. HSD11B1 gene polymorphisms in type 2 diabetes and metabolic syndrome—Do we have evidence for the association? Int. J. Diabetes Dev. Ctries. 2016 36 1 95 102 10.1007/s13410‑015‑0438‑5
    [Google Scholar]
  9. Anderson A. Walker B.R. 11β-HSD1 inhibitors for the treatment of type 2 diabetes and cardiovascular disease. Drugs 2013 73 13 1385 1393 10.1007/s40265‑013‑0112‑5 23990334
    [Google Scholar]
  10. Hong S.P. Han D. Chang K.H. Ahn S.K. A novel highly potent and selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, INU-101. Eur. J. Pharmacol. 2018 835 169 178 10.1016/j.ejphar.2018.08.005 30096297
    [Google Scholar]
  11. Cabrera Pérez L.C. Padilla-Martínez I.I. Cruz A. Correa Basurto J. Miliar García Á. Hernández Zavala A.A. Gómez López M. Rosales Hernández M.C. Design, synthesis, molecular docking and in vitro evaluation of benzothiazole derivatives as 11β-hydroxysteroid dehydrogenase type 1 inhibitors. Mol. Divers. 2020 24 4 1 14 10.1007/s11030‑019‑10006‑z 31664610
    [Google Scholar]
  12. Abbas A. Schini M. Ainsworth G. Brown S.R. Oughton J. Crowley R.K. Cooper M.S. Fairclough R.J. Eastell R. Stewart P.M. Effect of AZD4017, a selective 11β-HSD1 inhibitor, on bone turnover markers in postmenopausal osteopenia. J. Clin. Endocrinol. Metab. 2022 107 7 2026 2035 10.1210/clinem/dgac100 35275196
    [Google Scholar]
  13. Devang N. Banjan B. v K P. Discovery of novel inhibitor of 11 beta-hydroxysteroid dehydrogenase type 1 using in silico structure-based screening approach for the treatment of type 2 diabetes. J. Diabetes Metab. Disord. 2023 22 1 657 672 10.1007/s40200‑023‑01191‑8 37255841
    [Google Scholar]
  14. Prasoppokakorn T. Pitisuttithum P. Treeprasertsuk S. Pharmacological therapeutics: Current trends for metabolic dysfunction-associated fatty liver disease (MAFLD). J. Clin. Transl. Hepatol. 2021 9 6 939 946 10.14218/JCTH.2021.00189 34966657
    [Google Scholar]
  15. Omoboyede V. Ibrahim O. Umar H.I. Oke G.A. Onile O.S. Chukwuemeka P.O. Computer-aided analysis of quercetin mechanism of overcoming docetaxel resistance in docetaxel-resistant prostate cancer. J. Genet. Eng. Biotechnol. 2023 21 1 47 10.1186/s43141‑023‑00498‑6 37099169
    [Google Scholar]
  16. Chuanxin Z. Shengzheng W. Lei D. Duoli X. Jin L. Fuzeng R. Aiping L. Ge Z. Progress in 11β-HSD1 inhibitors for the treatment of metabolic diseases: A comprehensive guide to their chemical structure diversity in drug development. Eur. J. Med. Chem. 2020 191 112134 10.1016/j.ejmech.2020.112134 32088493
    [Google Scholar]
  17. Omoboyede V. Onile O.S. Oyeyemi B.F. Aruleba R.T. Fadahunsi A.I. Oke G.A. Unravelling the anti-inflammatory mechanism of Allium cepa: An integration of network pharmacology and molecular docking approaches. Mol Divers 2024 28 727 747 10.1007/s11030‑023‑10614‑w
    [Google Scholar]
  18. Wang Y. Bhuiya M.W. Zhou R. Yu O. Pterostilbene production by microorganisms expressing resveratrol O-methyltransferase. Ann. Microbiol. 2015 65 2 817 826 10.1007/s13213‑014‑0922‑z
    [Google Scholar]
  19. Kursvietiene L. Kopustinskiene D.M. Staneviciene I. Mongirdiene A. Kubová K. Masteikova R. Bernatoniene J. Anti-cancer properties of resveratrol: A focus on its impact on mitochondrial functions. Antioxidants 2023 12 12 2056 10.3390/antiox12122056 38136176
    [Google Scholar]
  20. Nawaz W. Zhou Z. Deng S. Ma X. Ma X. Li C. Shu X. Therapeutic versatility of resveratrol derivatives. Nutrients 2017 9 11 1188 10.3390/nu9111188 29109374
    [Google Scholar]
  21. Carpéné C. Les F. Cásedas G. Peiro C. Fontaine J. Chaplin A. Mercader J. López V. Resveratrol anti-obesity effects: Rapid inhibition of adipocyte glucose utilization. Antioxidants 2019 8 3 74 10.3390/antiox8030074 30917543
    [Google Scholar]
  22. VinithaThadhani M. Resveratrol in management of diabetes and obesity: Clinical applications, bioavailability, and nanotherapy. Resveratrol - Adding Life to Years, Not Adding Years to Life IntechOpen 2019
    [Google Scholar]
  23. Barber T.M. Kabisch S. Randeva H.S. Pfeiffer A.F.H. Weickert M.O. Implications of resveratrol in obesity and insulin resistance: A state-of-the-art review. Nutrients 2022 14 14 2870 10.3390/nu14142870 35889827
    [Google Scholar]
  24. Kim S. Chen J. Cheng T. Gindulyte A. He J. He S. Li Q. Shoemaker B.A. Thiessen P.A. Yu B. Zaslavsky L. Zhang J. Bolton E.E. PubChem 2023 update. Nucleic Acids Res. 2023 51 D1 D1373 D1380 10.1093/nar/gkac956 36305812
    [Google Scholar]
  25. Berman H.M. Westbrook J. Feng Z. Gilliland G. Bhat T.N. Weissig H. Shindyalov I.N. Bourne P.E. The Protein Data Bank. Nucleic Acids Res. 2000 28 1 235 242 10.1093/nar/28.1.235 10592235
    [Google Scholar]
  26. Sorensen B. Winn M. Rohde J. Shuai Q. Wang J. Fung S. Monzon K. Chiou W. Stolarik D. Imade H. Pan L. Deng X. Chovan L. Longenecker K. Judge R. Qin W. Brune M. Camp H. Frevert E.U. Jacobson P. Link J.T. Adamantane sulfone and sulfonamide 11-β-HSD1 Inhibitors. Bioorg. Med. Chem. Lett. 2007 17 2 527 532 10.1016/j.bmcl.2006.10.008 17070044
    [Google Scholar]
  27. Ojedele O.A. Umar H.I. baammi S. Metouekel A. Mengistie A.A. Bin Jardan Y.A. Shazly G.A. Victor O. Cheminformatics-aided discovery of potential allosteric site modulators of ubiquitin-specific protease 7. Sci. Rep. 2024 14 1 24995 10.1038/s41598‑024‑74851‑1 39443474
    [Google Scholar]
  28. Oraibi AI Karav S Khallouki F Exploration of rosmarinic acid as anti-esophageal cancer potential by use of network pharmacology and molecular docking approaches. Atl J Life Sci 2025 10.71005/b5jben88
    [Google Scholar]
  29. Onile O.S. Raji O. Omoboyede V. Fadahunsi A.I. Onile T.A. Momoh A.O. Structure-based discovery of phytocompounds from Azadirachta indica as potential inhibitors of thioredoxin glutathione reductase in Schistosoma mansoni. Cell Biochem Biophys 2024 10.1007/s12013‑024‑01577‑2
    [Google Scholar]
  30. Tripathi S.K. Muttineni R. Singh S.K. Extra precision docking, free energy calculation and molecular dynamics simulation studies of CDK2 inhibitors. J. Theor. Biol. 2013 334 87 100 10.1016/j.jtbi.2013.05.014 23727278
    [Google Scholar]
  31. Lipinski C.A. Lombardo F. Dominy B.W. Feeney P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2001 46 1-3 3 26 10.1016/S0169‑409X(00)00129‑0 11259830
    [Google Scholar]
  32. Lyne P.D. Lamb M.L. Saeh J.C. Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring. J. Med. Chem. 2006 49 16 4805 4808 10.1021/jm060522a 16884290
    [Google Scholar]
  33. Olukunle O.F. Olowosoke C.B. Khalid A. Oke G.A. Omoboyede V. Umar H.I. Identification of a 1,8-naphthyridine-containing compound endowed with the inhibition of p53-MDM2/X interaction signaling: A computational perspective. Mol Divers 2024 28 1109 1127 10.1007/s11030‑023‑10637‑3
    [Google Scholar]
  34. Bravo-Moraga F. Bedoya M. Zinovjev K. Tuñon I. Alzate-Morales J. Computational estimation of residence time on roniciclib and its derivatives against CDK2: Extending the use of classical and enhanced molecular dynamics simulations. ACS Omega 2025 10 16 16731 16747 10.1021/acsomega.5c00555
    [Google Scholar]
  35. Harris J.A. Liu R. Martins de Oliveira V. Vázquez- Montelongo E.A. Henderson J.A. Shen J. GPU-accelerated all-atom particle-mesh ewald continuous constant ph molecular dynamics in amber. J. Chem. Theory Comput. 2022 18 12 7510 7527 10.1021/acs.jctc.2c00586 36377980
    [Google Scholar]
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Exploration of Resveratrol Derivatives as Novel Therapeutic Modulators of 11β-Hydroxysteroid Dehydrogenase 1 Activity in Metabolic Dysregulation
Bentham Science Publishers ; https://doi.org/10.2174/0109298673376734250707194939
/content/journals/cmc/10.2174/0109298673376734250707194939
/content/journals/cmc/10.2174/0109298673376734250707194939
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  • Article Type:     Research Article
Keywords: obesity ; molecular dynamics simulation ; molecular docking ; 11β-hydroxysteroid dehydrogenase 1 ; type 2 diabetes ; metabolic disorders

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