TY - JOUR
T1 - Repurposing of natural products for spinocerebellar ataxia type 3 using integrated network pharmacology and in silico approaches
AU - Roney, Miah
AU - Mohd Hisam, Nur Shahirah
AU - Uddin, Md. Nazim
AU - Hamim, S. M. Istiaque
AU - Lim, Lee Wei
AU - Wong, Kah Hui
PY - 2026/2/5
Y1 - 2026/2/5
N2 - Spinocerebellar ataxia type 3 (SCA3) is a progressive inherited neurodegenerative disorder characterized by impaired coordination and balance due to cerebellar ataxia. Currently, there are no Food and Drug Administration (FDA)-approved drugs or curative treatments for SCA3. This study aimed to uncover the potential therapeutic mechanism of natural products (NP or NPs) against SCA3 using an integrative computational strategy combining network pharmacology, molecular docking, molecular dynamics (MD) simulation, principal component analysis (PCA), free energy landscape (FEL), dynamic cross-correlation matrix (DCCM), and Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) calculations. A total of 4,986 SCA3-related targets were retrieved from the GeneCards database, and 696 unique NP-related targets were obtained from SwissTargetPrediction and SuperPred databases. Protein–protein interaction (PPI) network analysis revealed 239 overlapping targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis identified the MAPK signaling pathway (hsa04010) as a key mechanism involving 33 critical proteins, including AKT1, TP53, TNF, EGFR, RELA, and MAPK1. Among the screened compounds, crocin exhibited the highest binding affinities with AKT1 (− 9.5 kcal/mol) and TP53 (− 6.6 kcal/mol) in docking studies. Further validation through MD simulation, PCA, FEL, DCCM, and MM/PBSA analysis confirmed the stability and strong interaction of crocin with these targets. This study highlights crocin as a promising candidate for SCA3 therapy and provides a foundation for future experimental validation.
AB - Spinocerebellar ataxia type 3 (SCA3) is a progressive inherited neurodegenerative disorder characterized by impaired coordination and balance due to cerebellar ataxia. Currently, there are no Food and Drug Administration (FDA)-approved drugs or curative treatments for SCA3. This study aimed to uncover the potential therapeutic mechanism of natural products (NP or NPs) against SCA3 using an integrative computational strategy combining network pharmacology, molecular docking, molecular dynamics (MD) simulation, principal component analysis (PCA), free energy landscape (FEL), dynamic cross-correlation matrix (DCCM), and Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) calculations. A total of 4,986 SCA3-related targets were retrieved from the GeneCards database, and 696 unique NP-related targets were obtained from SwissTargetPrediction and SuperPred databases. Protein–protein interaction (PPI) network analysis revealed 239 overlapping targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis identified the MAPK signaling pathway (hsa04010) as a key mechanism involving 33 critical proteins, including AKT1, TP53, TNF, EGFR, RELA, and MAPK1. Among the screened compounds, crocin exhibited the highest binding affinities with AKT1 (− 9.5 kcal/mol) and TP53 (− 6.6 kcal/mol) in docking studies. Further validation through MD simulation, PCA, FEL, DCCM, and MM/PBSA analysis confirmed the stability and strong interaction of crocin with these targets. This study highlights crocin as a promising candidate for SCA3 therapy and provides a foundation for future experimental validation.
UR - https://www.nature.com/articles/s41598-025-30652-8?utm_source=rct_congratemailt&utm_medium=email&utm_campaign=oa_20260220&utm_content=10.1038/s41598-025-30652-8
M3 - Article
SN - 2045-2322
VL - 16
JO - Scientific Reports
JF - Scientific Reports
M1 - 7332
ER -