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2000
Volume 22, Issue 1
  • ISSN: 1875-6921
  • E-ISSN: 1875-6913

Abstract

Introduction

Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by the development of benign tumors due to mutations in the NF1 gene, which encodes the tumor suppressor neurofibromin. This study aimed to identify novel inhibitors of neurofibromin through drug repurposing of clinical trial compounds from the Zinc15 database.

Methods

Utilizing advanced techniques, we conducted molecular docking PyRx and molecular dynamics simulations with GROMACS. Among the compounds analyzed, ZINC000261527152 (Tetrodotoxin) emerged as a promising candidate due to its binding affinity to NF1. Tetrodotoxin formed stable conventional and carbon-hydrogen bonds with key residues, including GLU 981, GLY 984, GLN 985, SER 1030, SER 1561, and ASN 1563. Molecular dynamics simulations confirmed the stability of the Tetrodotoxin-NF1 complex, with favorable RMSD, RMSF, radius of gyration (Rg), and solvent-accessible surface area (SASA) values over a 100 ns simulation period.

Results and Discussion

These results suggest that Tetrodotoxin could effectively inhibit neurofibromin, presenting a novel therapeutic approach for neurofibromatosis. However, despite the promising computational findings, further experimental validation through and studies is essential to confirm the efficacy and safety of Tetrodotoxin as a treatment for NF1.

Conclusion

This research underscores the utility of computational drug repurposing methodologies and their role in accelerating the discovery of novel treatments for genetic disorders, particularly neurofibromatosis, thereby potentially improving patient outcomes and quality of life.

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2025-10-18

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References

  1. BarkerD. WrightE. NguyenK. LoveD.R. SullivanS. GeorgeA.M. Neurofibromatosis type 1: Clinical, pathologic, and molecular features.J. Pathol.20172435526536
     [Google Scholar]
  2. UusitaloE. LeppävirtaJ. KallionpääR. A. UusitaloA. HirvonenE. VahteraJ. Mortality in neurofibromatosis 1: An analysis of 1,420 patients from a population-based study in Finland.J. Invest. Dermatol.20161364902906
     [Google Scholar]
  3. WalshM. KresakJ. Neurofibromatosis: A review of NF1, NF2, and schwannomatosis.J. Pediatr. Genet.20165209810410.1055/s‑0036‑157976627617150
     [Google Scholar]
  4. GutmannD.H. FernerR.E. ListernickR.H. KorfB.R. WoltersP.L. JohnsonK.J. Neurofibromatosis type 1.Nat. Rev. Dis. Primers2017311700410.1038/nrdp.2017.428230061
     [Google Scholar]
  5. PayneJ.M. HaebichK.M. MacKenzieR. WalshK.S. HearpsS.J.C. CoghillD. BartonB. PrideN.A. UllrichN.J. TonsgardJ.H. ViskochilD. SchorryE.K. KlesseL. FisherM.J. GutmannD.H. RosserT. PackerR.J. KorfB. AcostaM.T. BellgroveM.A. NorthK.N. Cognition, ADHD symptoms, and functional impairment in children and adolescents with neurofibromatosis type 1.J. Atten. Disord.20212581177118610.1177/108705471989438431838937
     [Google Scholar]
  6. Kehrer-SawatzkiH. CooperD.N. Challenges in the diagnosis of neurofibromatosis type 1 (NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants.Hum. Genet.2022141217719110.1007/s00439‑021‑02410‑z34928431
     [Google Scholar]
  7. LegiusE. MessiaenL. WolkensteinP. PanczaP. AveryR. A. BermanY. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: An international consensus recommendation.Genet Med.20212381506151310.1038/s41436‑021‑01170‑534012067
     [Google Scholar]
  8. JouhilahtiE.M. PeltonenS. HeapeA.M. PeltonenJ. The pathoetiology of neurofibromatosis 1.Am. J. Pathol.201117851932193910.1016/j.ajpath.2010.12.05621457932
     [Google Scholar]
  9. FordeC. Burkitt-WrightE. TurnpennyP.D. HaanE. EalingJ. MansourS. HolderM. LahiriN. DixitA. ProcterA. PacotL. VidaudD. CapriY. GerardM. DollfusH. SchaeferE. QuelinC. SigaudyS. BusaT. VeraG. DamajL. MessiaenL. StevensonD.A. DaviesP. Palmer-SmithS. CallawayA. WolkensteinP. PasmantE. UpadhyayaM. Natural history of NF1 c.2970_2972del p.(Met992del): confirmation of a low risk of complications in a longitudinal study.Eur. J. Hum. Genet.202230329129710.1038/s41431‑021‑01015‑434897289
     [Google Scholar]
  10. Darrigo JuniorL.G. FerrazV.E.F. CormediM.C.V. AraujoL.H.H. MagalhãesM.P.S. CarneiroR.C. SalesL.H.N. SuchmacherM. CunhaK.S. FilhoA.B. AzulayD.R. GellerM. Epidemiological profile and clinical characteristics of 491 Brazilian patients with neurofibromatosis type 1.Brain Behav.2022126e259910.1002/brb3.259935506373
     [Google Scholar]
  11. KangE. KimY.M. SeoG.H. OhA. YoonH.M. RaY.S. KimE.K. KimH. HeoS.H. KimG.H. OsbornM.J. TolarJ. YooH.W. LeeB.H. Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types.J. Hum. Genet.2020652798910.1038/s10038‑019‑0695‑031776437
     [Google Scholar]
  12. ScalaM. SchiavettiI. MadiaF. ChelleriC. PiccoloG. AccogliA. RivaA. SalpietroV. BocciardiR. MorcaldiG. Di DucaM. CaroliF. VerricoA. MilanaccioC. ViglizzoG. TraversoM. BaldassariS. ScudieriP. IacominoM. PiatelliG. MinettiC. StrianoP. GarrèM.L. De MarcoP. DianaM.C. CapraV. PavanelloM. ZaraF. Genotype-phenotype correlations in neurofibromatosis type 1: A single-center cohort study.Cancers (Basel)2021138187910.3390/cancers1308187933919865
     [Google Scholar]
  13. PradaC.E. RangwalaF.A. MartinL.J. LovellA.M. SaalH.M. SchorryE.K. HopkinR.J. Pediatric plexiform neurofibromas: Impact on morbidity and mortality in neurofibromatosis type 1.J. Pediatr.2012160346146710.1016/j.jpeds.2011.08.05121996156
     [Google Scholar]
  14. WilliamsK.B. LargaespadaD.A. New model systems and the development of targeted therapies for the treatment of neurofibromatosis Type 1-associated malignant peripheral nerve sheath tumors.Genes (Basel)202011547710.3390/genes1105047732353955
     [Google Scholar]
  15. WilsonB.N. JohnA.M. HandlerM.Z. SchwartzR.A. Neurofibromatosis type 1: New developments in genetics and treatment.J. Am. Acad. Dermatol.20218461667167610.1016/j.jaad.2020.07.10532771543
     [Google Scholar]
  16. AndersonM.K. JohnsonM. ThornburgL. HalfordZ. A review of selumetinib in the treatment of neurofibromatosis type 1-related plexiform neurofibromas.Ann. Pharmacother.202256671672610.1177/1060028021104629834541874
     [Google Scholar]
  17. GrossA.M. WoltersP.L. DombiE. BaldwinA. WhitcombP. FisherM.J. WeissB. KimA. BornhorstM. ShahA.C. MartinS. RoderickM.C. PichardD.C. CarbonellA. PaulS.M. TherrienJ. KapustinaO. HeiseyK. ClappD.W. ZhangC. PeerC.J. FiggW.D. SmithM. GlodJ. BlakeleyJ.O. SteinbergS.M. VenzonD.J. DoyleL.A. WidemannB.C. Selumetinib in children with inoperable plexiform neurofibromas.N. Engl. J. Med.2020382151430144210.1056/NEJMoa191273532187457
     [Google Scholar]
  18. GrossA.M. WidemannB.C. Clinical trial design in neurofibromatosis type 1 as a model for other tumor predisposition syndromes.Neurooncol. Adv.20202Suppl. 1i134i14010.1093/noajnl/vdaa01732642739
     [Google Scholar]
  19. RatnerN. MillerS.J. A RASopathy gene commonly mutated in cancer: The neurofibromatosis type 1 tumour suppressor.Nat. Rev. Cancer201515529030110.1038/nrc391125877329
     [Google Scholar]
  20. TamuraR. Current understanding of neurofibromatosis type 1, 2, and schwannomatosis.Int. J. Mol. Sci.20212211585010.3390/ijms2211585034072574
     [Google Scholar]
  21. WalkerJ.A. UpadhyayaM. Emerging therapeutic targets for neurofibromatosis type 1.Expert Opin. Ther. Targets201822541943710.1080/14728222.2018.146593129667529
     [Google Scholar]
  22. WidemannB. C. MarcusL. J. FisherM. J. WeissB. KimA. DombiE. Phase II study of selumetinib in pediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas.J. Clin. Oncol.202038111031682550
     [Google Scholar]
  23. PushpakomS. IorioF. EyersP.A. EscottK.J. HopperS. WellsA. DoigA. GuilliamsT. LatimerJ. McNameeC. NorrisA. SanseauP. CavallaD. PirmohamedM. Drug repurposing: Progress, challenges and recommendations.Nat. Rev. Drug Discov.2019181415810.1038/nrd.2018.16830310233
     [Google Scholar]
  24. WangC. HuangS. Drug development against metastatic cancers.Yale J. Biol. Med.201790111912328356899
     [Google Scholar]
  25. NosengoN. Can you teach old drugs new tricks?Nature2016534760731431610.1038/534314a27306171
     [Google Scholar]
  26. CorselloS.M. BittkerJ.A. LiuZ. GouldJ. McCarrenP. HirschmanJ.E. JohnstonS.E. VrcicA. WongB. KhanM. AsieduJ. NarayanR. MaderC.C. SubramanianA. GolubT.R. The Drug Repurposing Hub: A next-generation drug library and information resource.Nat. Med.201723440540810.1038/nm.430628388612
     [Google Scholar]
  27. BegleyC.G. AshtonM. BaellJ. BettessM. BrownM.P. CarterB. CharmanW.N. DavisC. FisherS. FrazerI. GautamA. JenningsM.P. KearneyP. KeeffeE. KellyD. LopezA.F. McGuckinM. ParkerM.W. RaynerC. RobertsB. RushJ.S. SullivanM. Drug repurposing: Misconceptions, challenges, and opportunities for academic researchers.Sci. Transl. Med.202113612eabd552410.1126/scitranslmed.abd552434550729
     [Google Scholar]
  28. KrishnamurthyN. GrimshawA.A. AxsonS.A. ChoeS.H. MillerJ.E. Drug repurposing: A systematic review on root causes, barriers and facilitators.BMC Health Serv. Res.202222197010.1186/s12913‑022‑08272‑z35906687
     [Google Scholar]
  29. AhmedF. KangI.S. KimK.H. AsifA. RahimC.S.A. SamantasingharA. MemonF.H. ChoiK.H. Drug repurposing for viral cancers: A paradigm of machine learning, deep learning, and virtual screening‐based approaches.J. Med. Virol.2023954e2869310.1002/jmv.2869336946499
     [Google Scholar]
  30. ChoudharyS. MalikY.S. TomarS. Identification of SARS-CoV-2 cell entry inhibitors by drug repurposing using in silico structure-based virtual screening approach.Front. Immunol.202011166410.3389/fimmu.2020.0166432754161
     [Google Scholar]
  31. Masoudi-SobhanzadehY. SalemiA. PourseifM.M. JafariB. OmidiY. Masoudi-NejadA. Structure-based drug repurposing against COVID-19 and emerging infectious diseases: Methods, resources and discoveries.Brief. Bioinform.2021226bbab11310.1093/bib/bbab11333993214
     [Google Scholar]
  32. PagadalaN.S. SyedK. TuszynskiJ. Software for molecular docking: A review.Biophys. Rev.2017929110210.1007/s12551‑016‑0247‑128510083
     [Google Scholar]
  33. KhanM. NizamaniA. ShahL. UllahI. WaqasM. HalimS.A. AtayaF.S. ElgazzarA.M. BatihaG.E.S. KhanA. Al-HarrasiA. Utilizing the drug repurposing strategy on current drugs: New leads for peptic ulcers via biochemical and biomolecular dynamics studies.J. Biomol. Struct. Dyn.202411410.1080/07391102.2024.230292638225797
     [Google Scholar]
  34. SterlingT. IrwinJ.J. ZINC 15-ligand discovery for everyone.J. Chem. Inf. Model.201555112324233710.1021/acs.jcim.5b0055926479676
     [Google Scholar]
  35. DallakyanS. OlsonA.J. Small-molecule library screening by docking with PyRx.Methods Mol. Biol.2015126324325010.1007/978‑1‑4939‑2269‑7_1925618350
     [Google Scholar]
  36. GalgaleS. ZainabR. KumarA. Molecular docking and dynamic simulation-based screening identifies inhibitors of targeted SARS-CoV-2 3clpro and human ace2.Int. J. Appl. Pharma.202329730810.22159/ijap.2023v15i6.48782
     [Google Scholar]
  37. NaschbergerA. BaradaranR. RuppB. CarroniM. The structure of neurofibromin isoform 2 reveals different functional states.Nature2021599788431531910.1038/s41586‑021‑04024‑x34707296
     [Google Scholar]
  38. JayasuryaS. Molecular docking and investigation of Boswellia serrata phytocompounds as cancer therapeutics to target growth factor receptors: An in silico approach.Int. J. Appl. Pharma.202317318310.22159/ijap.2023v15i4.47833
     [Google Scholar]
  39. HazraS. AzizA. SharmaS. Identification and screening of potential inhibitors obtained from Plumeria rubra L. compounds against type 2 diabetes mellitus.J. Biomol. Struct. Dyn.20234119100811009510.1080/07391102.2022.215392436510695
     [Google Scholar]
  40. BhowmikD. HasanM.A. Al-AminM. Molecular dynamics simulation for assessing the stability of protein-ligand complexes.J. Comput. Chem.2022432321335
     [Google Scholar]
  41. MullardA. New drugs on the horizon.Nat. Rev. Drug Discov.2021207485487
     [Google Scholar]
  42. AshburnT.T. ThorK.B. Drug repositioning: identifying and developing new uses for existing drugs.Nat. Rev. Drug Discov.20043867368310.1038/nrd146815286734
     [Google Scholar]
  43. EkinsS. WilliamsA.J. KrasowskiM.D. FreundlichJ.S. In silico repositioning of approved drugs for rare and neglected diseases.Drug Discov. Today2011167-829831010.1016/j.drudis.2011.02.01621376136
     [Google Scholar]
  44. FerreiraL. Dos SantosR. OlivaG. AndricopuloA. Molecular docking and structure-based drug design strategies.Molecules2015207133841342110.3390/molecules20071338426205061
     [Google Scholar]
  45. DasguptaB. DuganL.L. GutmannD.H. The neurofibromatosis 1 gene product neurofibromin regulates pituitary adenylate cyclase-activating polypeptide-mediated signaling in astrocytes.J. Neurosci.200323268949895410.1523/JNEUROSCI.23‑26‑08949.200314523097
     [Google Scholar]
  46. PhilpottC. TovellH. FraylingI.M. CooperD.N. UpadhyayaM. The NF1 somatic mutational landscape in sporadic human cancers.Hum. Genomics20171111310.1186/s40246‑017‑0109‑328637487
     [Google Scholar]
  47. CatterallW.A. WisedchaisriG. ZhengN. The chemical basis for tetrodotoxin and saxitoxin action on voltage-gated sodium channels.Trends Pharmacol. Sci.2017386433446
     [Google Scholar]
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Computational Screening of Clinical Drug Libraries for Neurofibromin Inhibition: A Molecular Docking and Dynamics Study for Neurofibromatosis Therapy
Curr. Pharm. and. Per. Med. 22, E18756921347485 (2025); https://doi.org/10.2174/0118756921347485250120053531
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  • Article Type:     Research Article
Keyword(s): Drug repurposing; molecular docking; molecular dynamics simulations; neurofibromatosis; neurofibromin inhibition; tetrodotoxin

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