A Computational Study of UDCA and TUDCA as Novel Therapeutic Agents for Parkinson's Disease
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterised by the loss of dopamine-producing neurons in the brain, resulting in motor disturbances such as tremors, rigidity, and slowed movement. Although current therapies can improve symptoms, many patients experience side effects and a gradual decline in treatment effectiveness over time. This study employs comprehensive in silico methods to evaluate the therapeutic potential of ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA), two bile acids with emerging neuroprotective properties. Molecular docking studies were conducted using AutoDock 1.5.7 software, and the ADMET properties of the compounds were assessed using SwissADME. Toxicity analyses of UDCA and TUDCA were performed using T.E.S.T 5.1.2 software. Molecular dynamics (MD) simulations of UDCA–protein complexes were carried out via the iMOD server and CABS-flex V 2.0. Molecular docking simulations revealed promising interactions between UDCA and TUDCA with Parkinson’s disease-associated proteins selected from the literature, including 1XQ8, 6CM4, 6RKB, and 4PYK. UDCA generally exhibited stronger binding affinities of −5.38, −8.99, −8.21, and −6.50 kcal/mol compared to TUDCA (−5.08, −7.07, −8.30, −5.94 kcal/mol), except in the case of MAO-B. Molecular dynamics simulations further supported the stability of the UDCA–protein complexes, with eigenvalues calculated as 3.97×10⁻⁷, 2.39×10⁻⁶, 1.59×10⁻⁵, and 9.02×10⁻⁵. Pharmacokinetic analyses indicated favourable properties for both UDCA and TUDCA, including high oral bioavailability and blood–brain barrier permeability. UDCA displayed slightly higher toxicity in aquatic organisms but exhibited comparable developmental and mutagenic risks to TUDCA. Collectively, these computational findings highlight the multi-target potential of UDCA and TUDCA in modulating neuroinflammatory processes, mitigating oxidative stress, and supporting mitochondrial integrity—mechanistic pathways central to PD pathogenesis.
Keywords:
Molecular docking, Mitochondrial dysfunction, Neurodegeneration, Parkinson's Disease, Taurodeoxycholic Acid, Ursodeoxycholic Acid
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References
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Castro-Caldas, M., Carvalho, A. N., Rodrigues, E., Henderson, C. J., Wolf, C. R., Rodrigues, C. M. P., & Gama, M. J. (2012). Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson’s disease. Molecular Neurobiology, 46(2), 475-486. https://doi.org/10.1007/s12035-012-8295-4
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Cruz-Vicente, P., Gonçalves, A. M., Ferreira, O., Queiroz, J. A., Silvestre, S., Passarinha, L. A., & Gallardo, E. (2021). Discovery of small molecules as membrane-bound catechol-O-methyltransferase inhibitors with interest in Parkinson’s disease: pharmacophore modeling, molecular docking and in vitro experimental validation studies. Pharmaceuticals, 15(1), 51. https://doi.org/10.3390/ph15010051
Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific reports, 7(1), 42717. https://doi.org/10.1038/srep42717
Dezsi, L., & Vecsei, L. (2017). Monoamine oxidase B inhibitors in Parkinson's disease. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders), 16(4), 425-439. https://doi.org/10.2174/1871527316666170124165222
Exner, N., Lutz, A. K., Haass, C., & Winklhofer, K. F. (2012). Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences. The EMBO Journal, 31(14), 3038-3062. https://doi.org/10.1038/emboj.2012.170
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Hisahara, S., & Shimohama, S. (2011). Dopamine Receptors and Parkinson′ s Disease. International Journal of Medicinal Chemistry, 2011(1), 403039. https://doi.org/10.1155/2011/403039
Jost, W. H. (2022). A critical appraisal of MAO-B inhibitors in the treatment of Parkinson’s disease. Journal of Neural Transmission, 129(5), 723-736. https://doi.org/10.1007/s00702-022-02465-w
Junior, E. R. D. O., Truzzi, E., Ferraro, L., Fogagnolo, M., Pavan, B., Beggiato, S., Rustichelli, C., Maretti, E., Lima, E. M., Leo, E., & Dalpiaz, A. (2020). Nasal administration of nanoencapsulated geraniol/ursodeoxycholic acid conjugate: Towards a new approach for the management of Parkinson’s disease. Journal of Controlled Release, 321, 540–552. https://doi.org/10.1016/j.jconrel.2020.02.033
Kaasinen, V., Aalto, S., Någren, K., Hietala, J., Sonninen, P., & Rinne, J. O. (2003). Extrastriatal dopamine D2 receptors in Parkinson's disease: a longitudinal study. Journal of Neural Transmission, 110(6), 591-601. https://doi.org/10.1007/s00702-003-0816-x
Kim, D. J., Yoon, S., Ji, S. C., Yang, J., Kim, Y. K., Lee, S., ... & Cho, J. Y. (2018). Ursodeoxycholic acid improves liver function via phenylalanine/tyrosine pathway and microbiome remodelling in patients with liver dysfunction. Scientific reports, 8(1), 11874. https://doi.org/10.1038/s41598-018-30349-1
Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., ... & Bolton, E. E. (2023). PubChem 2023 update. Nucleic acids research, 51(D1), D1373-D1380. https://doi.org/10.1093/nar/gkac956
Kuriata, A., Gierut, A. M., Oleniecki, T., Ciemny, M. P., Kolinski, A., Kurcinski, M., & Kmiecik, S. (2018). CABS-flex 2.0: a web server for fast simulations of flexibility of protein structures. Nucleic Acids Research, 46(W1), W338-W343. https://doi.org/10.1093/nar/gky356
Kwak, N., Lee, M. J., Kang, H. Y., & Lee, H. (2024). Cost-effectiveness Analysis of COMT-inhibitors as Adjuvant Treatments to Levodopa in Patients with Advanced Parkinson's Disease. Clinical Therapeutics, 46(9), 670-676. https://doi.org/10.1016/j.clinthera.2024.06.016
Lakshmi, Y. S., Prasanth, D. S. N. B. K., Kumar, K. T. S., Ahmad, S. F., Ramanjaneyulu, S., Rahul, N., & Pasala, P. K. (2023). Unravelling the molecular mechanisms of a quercetin nanocrystal for treating potential Parkinson’s disease in a rotenone model: supporting evidence of network pharmacology and in silico data analysis. Biomedicines, 11(10), 2756. https://doi.org/10.3390/biomedicines11102756
Lim, S. Y., & Klein, C. (2024). Parkinson’s disease is predominantly a genetic disease. Journal of Parkinson’s Disease, 14(3), 467-482. https://doi.org/10.3233/JPD-230376
Lopéz-Blanco, J. R., Garzón, J. I., & Chacón, P. (2011). iMod: multipurpose normal mode analysis in internal coordinates. Bioinformatics, 27(20), 2843-2850. https://doi.org/10.1093/bioinformatics/btr497
Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry, 30(16), 2785-2791. https://doi.org/10.1002/jcc.21256
Müller, T. (2015). Catechol-O-methyltransferase inhibitors in Parkinson’s disease. Drugs, 75(2), 157-174. https://doi.org/10.1007/s40265-014-0343-0
O'Boyle, N. M., Banck, M., James, C. A., Morley, C., Vandermeersch, T., & Hutchison, G. R. (2011). Open Babel: An open chemical toolbox. Journal of Cheminformatics, 3(1), 33. https://doi.org/10.1186/1758-2946-3-33
Payne, T., Sassani, M., Buckley, E., Moll, S., Anton, A., Appleby, M., ... & Bandmann, O. (2020). Ursodeoxycholic acid as a novel disease-modifying treatment for Parkinson’s disease: protocol for a two-centre, randomised, double-blind, placebo-controlled trial, The'UP'study. BMJ Open, 10(8), e038911. https://doi.org/10.1136/bmjopen-2020-038911
Qi, H., Shen, D., Jiang, C., Wang, H., & Chang, M. (2021). Ursodeoxycholic acid protects dopaminergic neurons from oxidative stress via regulating mitochondrial function, autophagy, and apoptosis in MPTP/MPP+-induced Parkinson’s disease. Neuroscience Letters, 741, 135493. https://doi.org/10.1016/j.neulet.2020.135493
Robakis, D., & Fahn, S. (2015). Defining the role of the monoamine oxidase-B inhibitors for Parkinson’s disease. CNS Drugs, 29(6), 433-441. https://doi.org/10.1007/s40263-015-0249-8
Rosa, A. I., Duarte-Silva, S., Silva-Fernandes, A., Nunes, M. J., Carvalho, A. N., Rodrigues, E., ... & Castro-Caldas, M. (2018). Tauroursodeoxycholic acid improves motor symptoms in a mouse model of Parkinson’s disease. Molecular Neurobiology, 55(12), 9139-9155. https://doi.org/10.1007/s12035-018-1062-4
Sathe, A. G., Tuite, P., Chen, C., Ma, Y., Chen, W., Cloyd, J., ... & Coles, L. D. (2020). Pharmacokinetics, safety, and tolerability of orally administered ursodeoxycholic acid in patients with Parkinson's disease—a pilot study. The Journal of Clinical Pharmacology, 60(6), 744-750. https://doi.org/10.1002/jcph.1575
Sharma, S., Kushwaha, K. P., & Chandra, R. (2019). Applications of BIOVIA materials studio, LAMMPS, and GROMACS in various fields of science and engineering. Molecular dynamics simulation of nanocomposites using BIOVIA materials studio, Lammps and Gromacs, 329-341. https://doi.org/10.1016/b978-0-12-816954-4.00007-3
Sharma, V. D., Patel, M., & Miocinovic, S. (2020). Surgical treatment of Parkinson's disease: devices and lesion approaches. Neurotherapeutics, 17(4), 1525-1538. https://doi.org/10.1007/s13311-020-00939-x
Shtilbans, A., Reintsch, W. E., Piscopo, V. E., Krahn, A. I., & Durcan, T. M. (2024). Combination of tauroursodeoxycholic acid, co-enzyme Q10 and creatine demonstrates additive neuroprotective effects in in-vitro models of Parkinson’s disease. Frontiers in Neuroscience, 18, 1492028. https://doi.org/10.3389/fnins.2024.1492028
Song, Z., Zhang, J., Xue, T., Yang, Y., Wu, D., Chen, Z., ... & Wang, Z. (2021). Different catechol-o-methyl transferase inhibitors in Parkinson's disease: a bayesian network meta-analysis. Frontiers in Neurology, 12, 707723. https://doi.org/10.3389/fneur.2021.707723
Stoker, T. B., & Barker, R. A. (2020). Recent developments in the treatment of Parkinson's Disease. F1000Research, 9, F1000-Faculty. https://doi.org/10.12688/f1000research.25634.1
Sveinbjornsdottir, S. (2016). The clinical symptoms of Parkinson's disease. Journal of Neurochemistry, 139, 318-324. https://doi.org/10.1111/jnc.13691
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Krishnamurthy, A., Sundaresan, N., Govindaraj, V., Raamakrishnan, S. and Janarthanan, M. (2025) “A Computational Study of UDCA and TUDCA as Novel Therapeutic Agents for Parkinson’s Disease”, International Journal of Advancement in Life Sciences Research, 8(4), pp. 22-37. doi: https://doi.org/10.31632/ijalsr.2025.v08i04.003.
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