Skip to content
2000
Volume 21, Issue 19
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Background

The Nrf2-Keap1 pathway holds great significance in antioxidant defense mechanisms. This pathway has emerged as a pivotal clinical target for the development of highly potent therapeutic agents for neurodegenerative diseases. The Keap1-Nrf2 inhibitors covalently bind to the Keap1 protein, leading to modifications in cysteine residues. This computational study focused on the investigation of coumarin derivatives through methods.

Objective

The aim of this study was to conduct an exploration of coumarin derivatives as potential Keap1 inhibitors in the context of Alzheimer's disease.

Methods

Coumarin derivatives were obtained from the ZINC 15 database in the sdf (simple dimension file) format. The docking process utilized the crystal structure of the Keap1 protein (PDB ID: 4XMB), which was sourced from the RCSB Protein Data Bank (https://www.rcsb.org/). Molecular docking was conducted using the AutoDock Vina1.5.7 software. Following this, the top ten coumarin derivatives with the highest binding energy underwent an ADME study, SAR study, toxicity study, and medicinal chemistry score study. In the study, resveratrol was employed as the standard drug.

Results

We sourced ligand molecules from the ZINC 15 database in pdf format, while the Keap1 protein, identified by its PDB ID: 4XMB, was obtained from the RCSB website (https://www.rcsb.org/) in pdb format. We used resveratrol as the standard drug for the molecular docking analysis. The molecular docking procedures were conducted using Autodock Vina 1.5.7 software.

Conclusion

Among the 75 coumarin derivatives assessed, 9 exhibited the most favourable binding energies towards Keap1. The top 9 derivatives of coumarin were further scrutinized in terms of their pharmacokinetic profiling and evaluation of bioactivity. Both compounds and exhibited noteworthy docking scores of -7.44 and -7.52 Kcal/mol, respectively. Our investigation revealed that all nine derivatives of coumarin exhibited properties characteristic of drug-like compounds. The investigation conducted suggested the potential development of coumarin derivatives as effective Keap1-Nrf2 inhibitors. Further validation of the computational findings requires both and studies.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/lddd/10.2174/0115701808338518241224060020
2025-01-10
2025-10-28

  • From This Site

    /content/journals/lddd/10.2174/0115701808338518241224060020
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. ScheltensP. De StrooperB. KivipeltoM. HolstegeH. ChételatG. TeunissenC.E. CummingsJ. van der FlierW.M. Alzheimer’s disease.Lancet2021397102841577159010.1016/S0140‑6736(20)32205‑4 33667416
     [Google Scholar]
  2. DeTureM.A. DicksonD.W. The neuropathological diagnosis of Alzheimer’s disease.Mol. Neurodegener.20191413210.1186/s13024‑019‑0333‑5 31375134
     [Google Scholar]
  3. NicholsE. SteinmetzJ.D. VollsetS.E. FukutakiK. ChalekJ. Abd-AllahF. AbdoliA. AbualhasanA. Abu-GharbiehE. AkramT.T. Al HamadH. AlahdabF. AlaneziF.M. AlipourV. AlmustanyirS. AmuH. AnsariI. ArablooJ. AshrafT. Astell-BurtT. AyanoG. Ayuso-MateosJ.L. BaigA.A. BarnettA. BarrowA. BauneB.T. BéjotY. BezabheW.M.M. BezabihY.M. BhagavathulaA.S. BhaskarS. BhattacharyyaK. BijaniA. BiswasA. BollaS.R. BoloorA. BrayneC. BrennerH. BurkartK. BurnsR.A. CámeraL.A. CaoC. CarvalhoF. Castro-de-AraujoL.F.S. Catalá-LópezF. CerinE. ChavanP.P. CherbuinN. ChuD-T. CostaV.M. CoutoR.A.S. DadrasO. DaiX. DandonaL. DandonaR. De la Cruz-GóngoraV. DhamnetiyaD. Dias da SilvaD. DiazD. DouiriA. EdvardssonD. EkholuenetaleM. El SayedI. El-JaafaryS.I. EskandariK. EskandariehS. EsmaeilnejadS. FaresJ. FaroA. FarooqueU. FeiginV.L. FengX. FereshtehnejadS-M. FernandesE. FerraraP. FilipI. FillitH. FischerF. GaidhaneS. GalluzzoL. GhashghaeeA. GhithN. GialluisiA. GilaniS.A. GlavanI-R. GnedovskayaE.V. GolechhaM. GuptaR. GuptaV.B. GuptaV.K. HaiderM.R. HallB.J. HamidiS. HanifA. HankeyG.J. HaqueS. HartonoR.K. HasaballahA.I. HasanM.T. HassanA. HayS.I. HayatK. HegazyM.I. HeidariG. Heidari-SoureshjaniR. HerteliuC. HousehM. HussainR. HwangB-F. IacovielloL. IavicoliI. IlesanmiO.S. IlicI.M. IlicM.D. IrvaniS.S.N. IsoH. IwagamiM. JabbarinejadR. JacobL. JainV. JayapalS.K. JayawardenaR. JhaR.P. JonasJ.B. JosephN. KalaniR. KandelA. KandelH. KarchA. KasaA.S. KassieG.M. KeshavarzP. KhanM.A.B. KhatibM.N. KhojaT.A.M. KhubchandaniJ. KimM.S. KimY.J. KisaA. KisaS. KivimäkiM. KoroshetzW.J. KoyanagiA. KumarG.A. KumarM. LakH.M. LeonardiM. LiB. LimS.S. LiuX. LiuY. LogroscinoG. LorkowskiS. LucchettiG. Lutzky SauteR. MagnaniF.G. MalikA.A. MassanoJ. MehndirattaM.M. MenezesR.G. MeretojaA. MohajerB. Mohamed IbrahimN. MohammadY. MohammedA. MokdadA.H. MondelloS. MoniM.A.A. MoniruzzamanM. MossieT.B. NagelG. NaveedM. NayakV.C. Neupane KandelS. NguyenT.H. OanceaB. OtstavnovN. OtstavnovS.S. OwolabiM.O. Panda-JonasS. Pashazadeh KanF. PasovicM. PatelU.K. PathakM. PeresM.F.P. PerianayagamA. PetersonC.B. PhillipsM.R. PinheiroM. PiradovM.A. PondC.D. PotashmanM.H. PottooF.H. PradaS.I. RadfarA. RaggiA. RahimF. RahmanM. RamP. RanasingheP. RawafD.L. RawafS. RezaeiN. RezapourA. RobinsonS.R. RomoliM. RoshandelG. SahathevanR. SahebkarA. SahraianM.A. SathianB. SattinD. SawhneyM. SaylanM. SchiavolinS. SeylaniA. ShaF. ShaikhM.A. ShajiK.S. ShannawazM. ShettyJ.K. ShigematsuM. ShinJ.I. ShiriR. SilvaD.A.S. SilvaJ.P. SilvaR. SinghJ.A. SkryabinV.Y. SkryabinaA.A. SmithA.E. SoshnikovS. SpurlockE.E. SteinD.J. SunJ. Tabarés-SeisdedosR. ThakurB. TimalsinaB. Tovani-PaloneM.R. TranB.X. TsegayeG.W. Valadan TahbazS. ValdezP.R. VenketasubramanianN. VlassovV. VuG.T. VuL.G. WangY-P. WimoA. WinklerA.S. YadavL. Yahyazadeh JabbariS.H. YamagishiK. YangL. YanoY. YonemotoN. YuC. YunusaI. ZadeyS. ZastrozhinM.S. ZastrozhinaA. ZhangZ-J. MurrayC.J.L. VosT. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019.Lancet Public Health202272e105e12510.1016/S2468‑2667(21)00249‑8 34998485
     [Google Scholar]
  4. BriggsR. KennellyS.P. O’NeillD. Drug treatments in Alzheimer’s disease.Clin. Med. 201616324725310.7861/clinmedicine.16‑3‑247 27251914
     [Google Scholar]
  5. Villavicencio TejoF. QuintanillaR.A. Contribution of the Nrf2 pathway on oxidative damage and mitochondrial failure in Parkinson and Alzheimer’s disease.Antioxidants2021107106910.3390/antiox10071069 34356302
     [Google Scholar]
  6. GoteS. ThapaS. DubeyS. NargundS.L. BiradarM.S. Computational investigation of quinazoline derivatives as Keap1 inhibitors for Alzheimer’s disease.Inform. Med. Unlocked20234110133410.1016/j.imu.2023.101334
     [Google Scholar]
  7. BreijyehZ. KaramanR. Comprehensive review on alzheimer’s disease: Causes and treatment.Molecules20202524578910.3390/molecules25245789 33302541
     [Google Scholar]
  8. LuM.C. JiJ.A. JiangZ.Y. YouQ.D. The Keap1–Nrf2–ARE pathway as a potential preventive and therapeutic target: An update.Med. Res. Rev.201636592496310.1002/med.21396 27192495
     [Google Scholar]
  9. YiannopoulouK.G. PapageorgiouS.G. Current and future treatments in alzheimer disease: An update.J. Cent. Nerv. Syst. Dis.20201210.1177/1179573520907397 32165850
     [Google Scholar]
  10. BalewskiŁ. SzultaS. JalińskaA. KornickaA. A mini-review: Recent advances in coumarin-metal complexes with biological properties.Front Chem.2021978177910.3389/fchem.2021.781779 34926402
     [Google Scholar]
  11. AlshiblH.M. Al-AbdullahE.S. HaibaM.E. AlkahtaniH.M. AwadG.E.A. MahmoudA.H. IbrahimB.M.M. BariA. VillingerA. Synthesis and evaluation of new coumarin derivatives as antioxidant, antimicrobial, and anti-inflammatory agents.Molecules20202514325110.3390/molecules25143251 32708787
     [Google Scholar]
  12. KonidalaS.K. KotraV. DandugaR.C.S.R. KolaP.K. Coumarin-chalcone hybrids targeting insulin receptor: Design, synthesis, anti-diabetic activity, and molecular docking.Bioorg. Chem.202010410420710.1016/j.bioorg.2020.104207 32947135
     [Google Scholar]
  13. KostovaI. RalevaS. GenovaP. ArgirovaR. Structure‐activity relationships of synthetic coumarins as HIV‐1 inhibitors.Bioinorg. Chem. Appl.20062006106827410.1155/BCA/2006/68274 17497014
     [Google Scholar]
  14. AminK.M. AwadallaF.M. EissaA.A.M. Abou-SeriS.M. HassanG.S. Design, synthesis and vasorelaxant evaluation of novel coumarin–pyrimidine hybrids.Bioorg. Med. Chem.201119206087609710.1016/j.bmc.2011.08.037 21908192
     [Google Scholar]
  15. HassaneinE.H.M. SayedA.M. HusseinO.E. MahmoudA.M. Coumarins as modulators of the Keap1/Nrf2/ARE signaling pathway.Oxid. Med. Cell. Longev.202020201212510.1155/2020/1675957 32377290
     [Google Scholar]
  16. Hadjipavlou-LitinaD. KontogiorgisC. PontikiE. DakanaliM. AkoumianakiA. KaterinopoulosH.E. Anti-inflammatory and antioxidant activity of coumarins designed as potential fluorescent zinc sensors.J. Enzyme Inhib. Med. Chem.200722328729210.1080/14756360601073914 17674809
     [Google Scholar]
  17. PatagarD.N. BatakurkiS.R. KusanurR. PatraS.M. SaravanakumarS. GhateM. Synthesis, antioxidant and anti-diabetic potential of novel benzimidazole substituted coumarin-3-carboxamides.J. Mol. Struct.2023127413458910.1016/j.molstruc.2022.134589
     [Google Scholar]
  18. SriharshaS.N. JainabN.H. BiradarM.S. ThapaS. VenkateshE.S. BidyeD.P. PujarG. DixitS. Novel β-L-1,3-thiazolidine pyrimidine nucleoside analogues: Design, synthesis, molecular docking, and anti-HIV activity.J. Mol. Struct.2023129413630410.1016/j.molstruc.2023.136304
     [Google Scholar]
  19. O’BoyleN.M. BanckM. JamesC.A. MorleyC. VandermeerschT. HutchisonG.R. Open Babel: An open chemical toolbox.J. Cheminform.2011313310.1186/1758‑2946‑3‑33 21982300
     [Google Scholar]
  20. GuedesI.A. de MagalhãesC.S. DardenneL.E. Receptor–ligand molecular docking.Biophys. Rev.201461758710.1007/s12551‑013‑0130‑2 28509958
     [Google Scholar]
  21. JainA.D. PottetiH. RichardsonB.G. KingsleyL. LucianoJ.P. RyuzojiA.F. LeeH. KrunicA. MesecarA.D. ReddyS.P. MooreT.W. Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators.Eur. J. Med. Chem.2015103325226810.1016/j.ejmech.2015.08.049 26363505
     [Google Scholar]
  22. ThapaS. NargundS.L. BiradarM.S. Molecular design and in-silico analysis of trisubstituted benzimidazole derivatives as ftsz inhibitor.J. Chem.202319
     [Google Scholar]
  23. YadavE. YadavP. KhanM.M.U. SinghH. VermaA. Resveratrol: A potential therapeutic natural polyphenol for neurodegenerative diseases associated with mitochondrial dysfunction.Front. Pharmacol.202213September92223210.3389/fphar.2022.922232 36188541
     [Google Scholar]
  24. EberhardtJ. Santos-MartinsD. TillackA.F. ForliS. AutoDock vina 1.2.0: New docking methods, expanded force field, and python bindings.J. Chem. Inf. Model.20216183891389810.1021/acs.jcim.1c00203 34278794
     [Google Scholar]
  25. TrottO. OlsonA.J. AutoDock vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.J. Comput. Chem.201031245546110.1002/jcc.21334 19499576
     [Google Scholar]
  26. SeeligerD. de GrootB.L. Ligand docking and binding site analysis with PyMOL and Autodock/Vina.J. Comput. Aided Mol. Des.201024541742210.1007/s10822‑010‑9352‑6 20401516
     [Google Scholar]
  27. DainaA. MichielinO. ZoeteV. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules.Sci. Rep.2017714271710.1038/srep42717 28256516
     [Google Scholar]
  28. ThapaS. NargundS.L. BiradarM.S. BanerjeeJ. KaratiD. In-silico investigation and drug likeliness studies of benzimidazole congeners: The new face of innovation.Inform. Med. Unlocked202338January10121310.1016/j.imu.2023.101213
     [Google Scholar]
  29. VrbanacJ. SlauterR. ADME in drug discovery. In: A Comprehensive Guide to Toxicology in Nonclinical Drug Development.Elsevier20163967
     [Google Scholar]
  30. LaguninA. StepanchikovaA. FilimonovD. PoroikovV. PASS: prediction of activity spectra for biologically active substances.Bioinformatics200016874774810.1093/bioinformatics/16.8.747 11099264
     [Google Scholar]
  31. GhoshS. TripathiP. TalukdarP. TalaptaraS.N. In silico study by using ProTox-II webserver for oral acute toxicity, organ toxicity, immunotoxicity, genetic toxicity endpoints, nuclear receptor signalling and stress response pathways of synthetic pyrethroids.World Sci. News201920191323551
     [Google Scholar]
/content/journals/lddd/10.2174/0115701808338518241224060020
Loading
In silico Investigation of Coumarin-based Compounds Targeting Keap1-Nrf2 Pathway Involved in the Development of Alzheimer’s Disease
Letters in Drug Design & Discovery 21, 4782 (2024); https://doi.org/10.2174/0115701808338518241224060020
/content/journals/lddd/10.2174/0115701808338518241224060020
/content/journals/lddd/10.2174/0115701808338518241224060020
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher's website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): Alzheimer’s disease; coumarin; Keap1; molecular docking; Nrf2; oxidative stress

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test