SavedAdd your journal

Journals / Uludağ Üniversitesi Tıp Fakültesi Dergisi / 2025 / Cilt: 51 Sayı: 2

Drug Repurposing Targeting Mitochondrial Dysfunction in Parkinson's Disease: FBXO7-Focused Approach Through Network Analysis and In Silico Molecular Docking

Parkinson Hastalığında Mitokondriyal Disfonksiyonu Hedefleyen İlaç Yeniden Konumlandırma: Network Analizi ve In Silico Moleküler Docking Aracılı FBXO7 Odaklı Bir Yaklaşım

Dilara Nemutlu Samur(Alanya Alaaddin Keykubat University, Faculty of Medicine, Department of Pharmacology, Antalya, Türkiye.)0000-0003-2630-6182
Pages
295–303
Publication Date
2025-08-28
🏛️Bibliographic metadata and full text access for this article are provided via DergiPark.
DergiPark Record ↗
✨

AI Summary & Key Takeaways

AI Insight
⚡ TL;DR(Too Long; Didn't Read)

Further experimental validation and structural optimization are required to enhance their therapeutic potential and minimize side effects, paving the way for novel therapeutic strategies in PD.

📌 3 Key Takeaways

🎯
Objective & Hypothesis:FBXO7 is a promising but underexplored therapeutic target in Parkinson’s disease (PD), having role in mitophagy, proteasomal degradation, and synaptic function.
📊
Key Findings & Data:This study aims to investigate the therapeutic potential of targeting mitochondrial dysfunction in PD through an FBXO7-centered drug repurposing approach.
💡
Conclusion & Impact:Further experimental validation and structural optimization are required to enhance their therapeutic potential and minimize side effects, paving the way for novel therapeutic strategies in PD.
🔬Design:Modeling & Simulation
📍Scope:Comprehensive Sample
⚙️Variables:FBXO7 · ilaç yeniden konumlandırma · mitokondriyal disfonksiyon

Abstract

FBXO7 is a promising but underexplored therapeutic target in Parkinson’s disease (PD), having role in mitophagy, proteasomal degradation, and synaptic function. This study aims to investigate the therapeutic potential of targeting mitochondrial dysfunction in PD through an FBXO7-centered drug repurposing approach. A protein-protein interaction (PPI) network was constructed using the STRING database, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to identify key pathways associated with FBXO7. Additionally, in silico molecular docking was conducted using the AutoDock Vina algorithm in SwissDock to evaluate the binding affinities of selected clinically approved drugs to FBXO7 and identify promising candidates for potential repurposing in PD treatment. Docking analysis identified several compounds with high binding affinity to FBXO7, including fluorometholone (-6.367 kcal/mol), bendroflumethiazide (-6.354 kcal/mol), lasofoxifene (-6.173 kcal/mol), penicillin V (-6.102 kcal/mol), hydromorphone (-6.067 kcal/mol), and cefamandole (-6.036 kcal/mol). These drugs are involved in biological pathways related to mitochondrial function, neuroinflammation, and cellular stress responses, highlighting their potential as disease-modifying agents in PD. However, limitations such as the potential for exacerbating disease progression or systemic side effects may restrict their direct repurposing. This study highlights several clinically approved drugs with high binding affinities to FBXO7, suggesting their potential for targeting mitochondrial dysfunction in PD. While some compounds may present challenges for or direct use, their molecular interactions offer valuable insights for developing novel mitochondrial-targeted therapies. Further experimental validation and structural optimization are required to enhance their therapeutic potential and minimize side effects, paving the way for novel therapeutic strategies in PD.

Özet

FBXO7, mitofaji, proteazomal degradasyon ve sinaptik işlevlerde rol oynayan, Parkinson hastalığı (PH)'nda umut vadeden ancak yeterince araştırılmamış bir terapötik hedeftir. Parkinson hastalığında PH’de mitokondriyal disfonksiyonu hedef alan, FBXO7 merkezli bir ilaç yeniden konumlandırma yaklaşımının terapötik potansiyelini araştırmayı amaçlamaktadır. Bu amaçla, STRING veritabanı kullanılarak bir protein-protein etkileşim (PPI) ağı oluşturulmuş; ardından FBXO7 ile ilişkili temel biyolojik yolları belirlemek için Gen Ontolojisi (GO) ve KEGG zenginleştirme analizleri gerçekleştirilmiştir. Ayrıca, seçilen klinik olarak onaylı ilaçların FBXO7’ye bağlanma afinitelerini değerlendirmek ve PH tedavisi için yeniden konumlandırılmaya uygun adayları belirlemek üzere SwissDock üzerinden AutoDock Vina algoritması kullanılarak in silico moleküler docking çalışmaları yapılmıştır. Docking analizi sonucunda FBXO7’ye yüksek bağlanma afinitesi gösteren çeşitli bileşikler tanımlanmıştır: florometolon (–6,367 kcal/mol), bendroflumetiyazid (–6,354 kcal/mol), lasofoksifen (–6,173 kcal/mol), penisilin V (–6,102 kcal/mol), hidromorfon (–6,067 kcal/mol) ve sefamandol (–6,036 kcal/mol). Bu ilaçlar, mitokondri işlevi, nöroinflamasyon ve hücresel stres yanıtlarıyla ilişkili biyolojik yollarla bağlantılı olup, PH'de hastalık modifiye edici ajanlar olma potansiyeline sahiptir. Ancak, hastalık progresyonunu kötüleştirme veya sistemik yan etkiler gibi sınırlılıklar doğrudan yeniden kullanımını kısıtlayabilir. Bu çalışma, FBXO7 ile yüksek bağlanma afinitesi gösteren klinik olarak onaylı çeşitli ilaçları ortaya koyarak, bunların PH’de mitokondriyal disfonksiyonu hedeflemek için potansiyel taşıdığını göstermektedir. Bazı bileşiklerin doğrudan kullanımıyla ilgili zorluklar bulunsa da, elde edilen moleküler etkileşim verileri mitokondri odaklı yeni tedavi stratejileri geliştirmek için değerli bilgiler sunmaktadır. Terapötik potansiyelin artırılması ve yan etkilerin azaltılması için ileri düzey deneysel doğrulama ve yapısal optimizasyon gereklidir; bu da PPH için yeni tedavi yaklaşımlarının önünü açabilir.

🔖

Cite This Article

Samur, D. N., *, D. N. S. (2025). Drug Repurposing Targeting Mitochondrial Dysfunction in Parkinson's Disease: FBXO7-Focused Approach Through Network Analysis and In Silico Molecular Docking. Uludağ Üniversitesi Tıp Fakültesi Dergisi, Cilt: 51 Sayı: 2, 295–303. https://doi.org/10.32708/uutfd.1707053

📄 Full Text PDF Viewer

📄

PDF görüntüleyici hazırlanıyor...

References (42)

  1. Koeglsperger T, Rumpf S-L, Schließer P, et al. Neuropathology of incidental Lewy body & prodromal Parkinson’s disease. Molecular Neurodegeneration. 2023/05/12 2023;18(1):32. doi:10.1186/s13024-023-00622-7
  2. Büeler H. Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease. Exp Neurol. Aug 2009;218(2):235-46. doi:10.1016/j.expneurol.2009.03.006
  3. Henrich MT, Oertel WH, Surmeier DJ, Geibl FF. Mitochondrial dysfunction in Parkinson's disease - a key disease hallmark with therapeutic potential. Mol Neurodegener. Nov 11 2023;18(1):83. doi:10.1186/s13024-023-00676-7
  4. Choong C-J, Mochizuki H. Involvement of Mitochondria in Parkinson’s Disease. International Journal of Molecular Sciences. 2023;24(23):17027.
  5. Kraus F, Goodall EA, Smith IR, et al. PARK15/FBXO7 is dispensable for PINK1/Parkin mitophagy in iNeurons and HeLa cell systems. EMBO Rep. Aug 3 2023;24(8):e56399. doi:10.15252/embr.202256399
  6. Fonzo AD, Dekker M, Montagna P, et al. FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology. 2009;72(3):240-245.
  7. Vingill S, Brockelt D, Lancelin C, et al. Loss of FBXO7 (PARK15) results in reduced proteasome activity and models a parkinsonism-like phenotype in mice. Embo j. Sep 15 2016;35(18):2008-25. doi:10.15252/embj.201593585
  8. Joseph S, Schulz JB, Stegmüller J. Mechanistic contributions of FBXO7 to Parkinson disease. J Neurochem. Jan 2018;144(2):118-127. doi:10.1111/jnc.14253
  9. Han M, Jung S, Lee D. Drug repurposing for Parkinson’s disease by biological pathway based edge-weighted network proximity analysis. Scientific Reports. 2024/09/11 2024;14(1):21258. doi:10.1038/s41598-024-71922-1
  10. MacMahon M, Hwang W, Yim S, et al. An in silico drug repurposing pipeline to identify drugs with the potential to inhibit SARS-CoV-2 replication. Informatics in Medicine Unlocked. 2023/01/01/ 2023;43:101387. doi:https://doi.org/10.1016/j.imu.2023.101387
  11. Liu Y, Lear TB, Verma M, et al. Chemical inhibition of FBXO7 reduces inflammation and confers neuroprotection by stabilizing the mitochondrial kinase PINK1. JCI Insight. Jun 4 2020;5(11)doi:10.1172/jci.insight.131834
  12. Xu Y, Zhi F, Mao J, et al. δ-opioid receptor activation protects against Parkinson's disease-related mitochondrial dysfunction by enhancing PINK1/Parkin-dependent mitophagy. Aging (Albany NY). Nov 10 2020;12(24):25035-25059. doi:10.18632/aging.103970
  13. Navarro E, Esteras N. A new mutation in the Parkinson's-related FBXO7 gene impairs mitochondrial and proteasomal function. Febs j. Jun 2024;291(12):2562-2564. doi:10.1111/febs.17155
  14. Shojaee S, Sina F, Banihosseini SS, et al. Genome-wide linkage analysis of a Parkinsonian-pyramidal syndrome pedigree by 500 K SNP arrays. Am J Hum Genet. Jun 2008;82(6):1375-84. doi:10.1016/j.ajhg.2008.05.005
  15. Di Fonzo A, Dekker MC, Montagna P, et al. FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology. Jan 20 2009;72(3):240-5. doi:10.1212/01.wnl.0000338144.10967.2b
  16. Imberechts D, Vandenberghe W. Defects in PINK-PRKN-PARK7/DJ-1-dependent mitophagy and autosomal recessive Parkinson disease. Autophagy. Jun 2023;19(6):1872-1873. doi:10.1080/15548627.2022.2139129
  17. Minigh J. Fluorometholone. In: Enna SJ, Bylund DB, eds.xPharm: The Comprehensive Pharmacology Reference. Elsevier; 2007:1-4.
  18. Claros S, Gil A, Martinelli M, et al. Impact of Glucocorticoidon a Cellular Model of Parkinson's Disease: Oxidative Stressand Mitochondrial Function. Brain Sci. Aug 222021;11(8)doi:10.3390/brainsci11081106
  19. Tentillier N, Etzerodt A, Olesen MN, et al. Anti-InflammatoryModulation of Microglia via CD163-Targeted GlucocorticoidsProtects Dopaminergic Neurons in the 6-OHDA Parkinson's Disease Model. J Neurosci. Sep 7 2016;36(36):9375-90. doi:10.1523/jneurosci.1636-16.2016
  20. Vyas S, Rodrigues AJ, Silva JM, et al. Chronic Stress andGlucocorticoids: From Neuronal Plasticity to Neurodegeneration. Neural Plasticity. 2016/01/01 2016;2016(1):6391686. doi:https://doi.org/10.1155/2016/6391686
  21. Choi GE, Han HJ. Glucocorticoid impairs mitochondrialquality control in neurons. Neurobiol Dis. May 2021;152:105301. doi:10.1016/j.nbd.2021.105301
  22. Schlagel CA. COMPARATIVE EFFICACY OF TOPICAL ANTI-INFLAMMATORY CORTICOSTEROIDS. J Pharm Sci. Mar 1965;54:335-54. doi:10.1002/jps.2600540302
  23. DeLoach T, Beall J. Diuretics: A possible keystone in upholding cognitive health. Ment Health Clin. Jan 2018;8(1):33-40. doi:10.9740/mhc.2018.01.033
  24. Gennari L. Lasofoxifene: a new type of selective estrogen receptor modulator for the treatment of osteoporosis. Drugs Today (Barc). Jun 2006;42(6):355-67. doi:10.1358/dot.2006.42.6.973583
  25. Simpkins JW, Yi KD, Yang SH, Dykens JA. Mitochondrialmechanisms of estrogen neuroprotection. Biochim BiophysActa. Oct 2010;1800(10):1113-20. doi:10.1016/j.bbagen.2009.11.013
  26. Villa A, Vegeto E, Poletti A, Maggi A. Estrogens,Neuroinflammation, and Neurodegeneration. Endocr Rev. Aug2016;37(4):372-402. doi:10.1210/er.2016-1007
  27. Mei R, Lou P, You G, Jiang T, Yu X, Guo L. 17β-Estradiol Induces Mitophagy Upregulation to Protect Chondrocytes viathe SIRT1-Mediated AMPK/mTOR Signaling Pathway. Front Endocrinol (Lausanne). 2020;11:615250.doi:10.3389/fendo.2020.615250
  28. Gillies GE, Pienaar IS, Vohra S, Qamhawi Z. Sex differences inParkinson's disease. Front Neuroendocrinol. Aug2014;35(3):370-84. doi:10.1016/j.yfrne.2014.02.002
  29. Arevalo MA, Santos-Galindo M, Lagunas N, Azcoitia I,Garcia-Segura LM. Selective estrogen receptor modulators asbrain therapeutic agents. Journal of Molecular Endocrinology. 01 Feb. 2011 2011;46(1):R1-R9. doi:10.1677/JME-10-0122
  30. Cosman F, Baz-Hecht M, Cushman M, et al. Short-term effectsof estrogen, tamoxifen and raloxifene on hemostasis: arandomized-controlled study and review of the literature. Thrombosis Research. 2005/01/01/ 2005;116(1):1-13. doi:https://doi.org/10.1016/j.thromres.2004.09.014
  31. Yimer EM, Hishe HZ, Tuem KB. Repurposing of the β-Lactam Antibiotic, Ceftriaxone for Neurological Disorders: A Review.Front Neurosci. 2019;13:236. doi:10.3389/fnins.2019.00236
  32. Rothstein JD, Patel S, Regan MR, et al. Beta-lactam antibioticsoffer neuroprotection by increasing glutamate transporterexpression. Nature. Jan 6 2005;433(7021):73-7. doi:10.1038/nature03180
  33. Stock ML, Fiedler KJ, Acharya S, et al. Antibiotics acting asneuroprotectants via mechanisms independent of their anti-infective activities. Neuropharmacology. 2013/10/01/2013;73:174-182. doi:https://doi.org/10.1016/j.neuropharm.2013.04.059
  34. Karabulut S, Filiz AK. The effect of penicillin-induced epileptiform activity on proinflammatory cytokines levels in therat brain. Cumhuriyet Science Journal. March 2021;42(1):1-6.doi:10.17776/csj.775122
  35. Murray A, Hagen NA. Hydromorphone. Journal of Pain andSymptom Management. 2005;29(5):57-66. doi:10.1016/j.jpainsymman.2005.01.007
  36. Vicente-Sanchez A, Segura L, Pradhan AA. The delta opioidreceptor tool box. Neuroscience. 2016/12/03/ 2016;338:145-159. doi:https://doi.org/10.1016/j.neuroscience.2016.06.028
  37. Zhang J, Gibney GT, Zhao P, Xia Y. Neuroprotective role ofdelta-opioid receptors in cortical neurons. Am J Physiol CellPhysiol. Jun 2002;282(6):C1225-34. doi:10.1152/ajpcell.00226.2001
  38. Huang JZ, Ren Y, Xu Y, et al. The delta-opioid receptor andParkinson's disease. CNS Neurosci Ther. Dec2018;24(12):1089-1099. doi:10.1111/cns.13045
  39. Lee KA, Ganta N, Horton JR, Chai E. Evidence forNeurotoxicity Due to Morphine or Hydromorphone Use inRenal Impairment: A Systematic Review. J Palliat Med. Nov2016;19(11):1179-1187. doi:10.1089/jpm.2016.0101
  40. Guenther S, Mickle TC, Barrett AC, et al. Pharmacokineticsand Abuse Potential of Asalhydromorphone, a Novel Prodrugof Hydromorphone, After Intranasal Administration inRecreational Drug Users. Pain Med. Mar 1 2020;21(3):511-520. doi:10.1093/pm/pnz066
  41. Martin EJ, Vaughan CL, Atayee R, Hirst JM, O'Donnell K,Edmonds KP. Hydromorphone-induced chorea as an atypicalpresentation of opioid neurotoxicity: A case report and reviewof the literature. Palliat Med. Oct 2018;32(9):1529-1532. doi:10.1177/0269216318786861
  42. Fainsinger R, Schoeller T, Boiskin M, Bruera E. Palliative careround: cognitive failure and coma after renal failure in a patient receiving captopril and hydromorphone. Journal of palliativecare. 1993;9(1):53-55.