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Tiliacorinine as a Promising Candidate for Cholangiocarcinoma Therapy via Oxidative Stress Molecule Modulation: A
Tavisa Boonsit1, Moragot Chatatikun1,2, Suphasarang Sirirattanakul1,2
1School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80161, Thailand.
Abstract:
Cholangiocarcinoma (CCA), an aggressive biliary tract cancer whose prevalence is rising, particularly in Thailand, is marked by elevated oxidative stress driven by chronic inflammation, parasitic infections, and dysregulated redox signaling. This study investigates the anticancer potential of tiliacorinine using a silico approach, including drug-likeness, ADMET, network pharmacology, molecular docking, and dynamics simulations. Tiliacorinine and 216 predicted targets were identified, with 79 overlapping CCA-related genes from GeneCards. GO and KEGG analyses revealed involvement in cell migration, membrane structure, kinase activity, and cancer-associated pathways. Network and PPI analyses identified ten key targets, including SRC, HIF1A, HSP90AA1, NFKB1, MTOR, MMP9, MMP2, PIK3CA, ICAM1, and MAPK1. Tiliacorinine showed the strongest affinity for MTOR (-10.78 kcal/mol, Ki = 12.62 nM), binding at the same site as known inhibitors with superior energy and specificity, supported by hydrogen bonding at ASP950 and hydrophobic interactions. Tiliacorinine also demonstrated strong binding to SRC, MMP9, and MAPK1. Molecular dynamics simulations revealed stable binding of tiliacorinine to MTOR, particularly at residues ASP950, TRP1086, and PHE1087. Comparative analysis with the MTOR-GDC-0980 complex confirmed consistent interaction patterns, reinforcing the structural stability and specificity of tiliacorinine. These results highlight its strong pharmacological potential and support its candidacy as a promising lead compound for cholangiocarcinoma therapy.
Insights
Tiliacorinine shows promise as a cholangiocarcinoma (CCA) treatment. Computational studies reveal its strong binding to key cancer targets like MTOR, suggesting potential as a novel therapeutic lead compound.
Area of Science:
- Pharmacology
- Computational Chemistry
- Oncology
Background:
- Cholangiocarcinoma (CCA) is an aggressive biliary tract cancer with increasing prevalence, especially in Thailand.
- Elevated oxidative stress, chronic inflammation, and parasitic infections contribute to CCA development.
- Understanding the molecular mechanisms and identifying novel therapeutic targets is crucial for effective CCA treatment.
Purpose of the Study:
- To investigate the anticancer potential of tiliacorinine against cholangiocarcinoma (CCA) using a comprehensive in silico approach.
- To identify potential molecular targets of tiliacorinine and evaluate its drug-likeness and pharmacokinetic properties.
- To assess the binding affinity and stability of tiliacorinine to key targets using molecular docking and dynamics simulations.
Main Methods:
- In silico drug-likeness and ADMET prediction.
- Network pharmacology, GeneCards, Gene Ontology (GO), and KEGG pathway analyses.
- Molecular docking, protein-protein interaction (PPI) network analysis, and molecular dynamics simulations.
Main Results:
- Tiliacorinine exhibited favorable drug-likeness and ADMET profiles.
- Network analysis identified ten key targets, including MTOR, SRC, HIF1A, and MAPK1, involved in CCA pathways.
- Tiliacorinine demonstrated strong binding affinity to MTOR, comparable to known inhibitors, with stable interactions observed in molecular dynamics simulations.
Conclusions:
- Tiliacorinine possesses significant pharmacological potential as an anticancer agent.
- Its strong binding affinity and stable interactions with key targets like MTOR support its candidacy as a promising lead compound for cholangiocarcinoma therapy.
- Further experimental validation is warranted to confirm the therapeutic efficacy of tiliacorinine in preclinical and clinical settings.
