Cancer remains a leading cause of mortality worldwide, with conventional therapies showing limited efficacy and high toxicity. The increasing incidence and therapeutic resistance necessitate alternative strategies. In this regard, phytochemicals have emerged as potential sources of developing safer and novel anti-cancer agents. This study employs a structure-based drug design approach, integrating molecular docking, molecular dynamics (MD) simulations, and in silico profiling, to investigate the anti-cancer potential of metabolites from Curcuma caesia rhizomes. The research targets key cancer-associated proteins, Matrix Metalloproteinase-9 (MMP9) and Glucose-Regulated Protein 78 (GRP78), identified through expression analysis, functional network mapping, and pathway enrichment as critical mediators of cancer progression and metastasis. A comprehensive molecular docking analysis of 101 bioactive compounds from C. caesia rhizomes identified curcumin and bis-demethoxycurcumin as promising candidates, demonstrating high binding affinities and stable interactions with MMP9 and GRP78. MD simulations further validated the stability and robustness of these interactions under dynamic physiological conditions. Pharmacological profiling, including ADMET analysis, Lipinski's rule compliance, and bioactivity scoring, revealed favorable drug-like properties for both compounds, including strong absorption, distribution, low toxicity, and potential therapeutic activities such as enzyme inhibition and nuclear receptor-mediated processes. KEGG pathway enrichment analysis confirmed their involvement in key biological pathways linked to cancer progression, underscoring their therapeutic potential. The findings highlight curcumin and bis-demethoxycurcumin as promising phytochemical candidates for cancer therapy, capable of modulating MMP9 and GRP78 to suppress tumor progression. While these results provide a solid basis for their therapeutic potential, further experimental studies and clinical trials are crucial to confirm their efficacy and safety for human applications.

• MeSH
• chaperon endoplazmatického retikula BiP MeSH
• Curcuma * chemie   metabolismus   MeSH
• diarylheptanoidy farmakologie   MeSH
• fytogenní protinádorové látky * farmakologie   chemie   MeSH
• kurkumin analogy a deriváty   farmakologie   chemie   MeSH
• lidé MeSH
• matrixová metaloproteinasa 9 * metabolismus   chemie   MeSH
• nádory * farmakoterapie   metabolismus   MeSH
• objevování léků * metody   MeSH
• oddenek * chemie   metabolismus   MeSH
• proteiny teplotního šoku * metabolismus   chemie   MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chaperon endoplazmatického retikula BiP MeSH
• demethoxycurcumin MeSH Prohlížeč
• diarylheptanoidy MeSH
• fytogenní protinádorové látky * MeSH
• HSPA5 protein, human MeSH Prohlížeč
• kurkumin MeSH
• matrixová metaloproteinasa 9 * MeSH
• MMP9 protein, human MeSH Prohlížeč
• proteiny teplotního šoku * MeSH

Neurodegenerative disorders (NDs) are typically characterized by progressive loss of neuronal function and the deposition of misfolded proteins in the brain and peripheral organs. They are molecularly classified based on the specific proteins involved, underscoring the critical role of protein-processing systems in their pathogenesis. Alpha-synuclein (α-syn) is a neural protein that is crucial in initiating and progressing various NDs by directly or indirectly regulating other ND-associated proteins. Therefore, reducing the α-syn aggregation can be an excellent option for combating ND initiation and progression. This study presents an in silico phytochemical-based approach for discovering novel neuroprotective agents from bioactive compounds of the Lamiaceae family, highlighting the potential of computational methods such as functional networking, pathway enrichment analysis, molecular docking, and simulation in therapeutic discovery. Functional network and enrichment pathway analysis established the direct or indirect involvement of α-syn in various NDs. Furthermore, molecular docking interaction and simulation studies were conducted to screen 85 major bioactive compounds of the Lamiaceae family against the α-syn aggregation. The results showed that five compounds (α-copaene, γ-eudesmol, carnosol, cedryl acetate, and spathulenol) had a high binding affinity towards α-syn with potential inhibitory activity towards its aggregation. MD simulations validated the stability of the molecular interactions determined by molecular docking. In addition, in silico pharmacokinetic analysis underscores their potential as promising drug candidates, demonstrating excellent blood-brain barrier (BBB) permeability, bioactivity, and reduced toxicity. In summary, this study identifies the most suitable compounds for targeting the α-syn aggregation and recommends these compounds as potential therapeutic agents against various NDs, pending further in vitro and in vivo validation.

• Klíčová slova
• MD simulation, functional network analysis, molecular docking, neuroprotective agent, pathway enrichment analysis, phytochemical,
• Publikační typ
• časopisecké články MeSH