In-Silico Analysis of Mangiferin Derivatives for Inhibition of the Wnt/Beta-Catenin Pathway to Prevent Carcinogenesis in HCC Using Molecular Docking

MARTIN OLOAN ADIKARA LUMBAN TOBING, Prof. Dr.rer.nat Harno Dwi Pranowo, M.S.; Prof. Tri Joko Raharjo, S.Si., M.Si., Ph.D.

2024 | Skripsi | KIMIA

Penelitian in-silico mengenai penambatan molekul dari turunan mangiferin dengan komponen jalur Wnt/?-catenin untuk mencegah karsinogenesis HCC telah dilakukan secara menyeluruh dalam penelitian ini. Penelitian ini bertujuan untuk memvalidasi bagaimana polifenol alami seperti turunan mangiferin dapat digunakan untuk menghambat jalur biologis, serta untuk mensimulasikan kompleks protein dalam lingkungan yang relevan guna memverifikasi efek inhibisinya.  

Penelitian dimulai dengan mengumpulkan ligan dari PubChem dan reseptor target dari RCSB PDB. Setiap struktur diimpor ke dalam YASARA dan diedit untuk mencapai kondisi yang bersih dan dimaksimalkan energinya. Ligan dan reseptor target didocking satu sama lain, menghasilkan total 20 kompleks unik. Setelah molecular docking, dua kompleks dengan energi pengikatan terbaik diekspor untuk melanjutkan ke molecular dynamics. Interaksi residu kemudian dipetakan menggunakan Biovia Discovery Studio untuk membantu visualisasi.

Sebagai kesimpulan, dua kompleks terbaik adalah homomangiferin-WT1 dan neomangiferin-WT1 dengan energi pengikatan masing-masing -8,353 kcal/mol dan -8,347 kcal/mol, dengan keduanya menunjukkan lokasi pengikatan dalam domain zinc-finger. Dinamika molekul menunjukkan bahwa homomangiferin menghasilkan interaksi yang lebih stabil dengan WT1 dibanding neomangiferin.

The in-silico molecular docking research regarding mangiferin derivatives with components of the Wnt/?-catenin pathway in order to prevent HCC carcinogenesis was thoroughly conducted in this thesis. It aimed to validate how natural polyphenols, such as mangiferin derivatives, can be utilized for inhibition of biological pathways, and also to simulate the protein complexes in a relevant environment to verify their inhibitory effects.

The research started with the ligands gathered from PubChem and the target receptors from RCSB PDB. Each structure was imported into YASARA and edited in order to achieve its clean state and energy minimized. The ligands and the target receptors were docked with each other, resulting in a total of 20 unique complexes. After molecular docking, the two complexes exhibiting the best binding energies were exported to proceed to molecular dynamics. The residue interaction was then plotted into Biovia Discovery Studio to assist in the visualization.

In conclusion, the two best complexes were homomangiferin-WT1 and neomangiferin-WT1 with binding energies of -8.353 kcal/mol and -8.347 kcal/mol respectively, with both showing binding sites in the zinc-finger domain. Molecular dynamics simulations demonstrate that homomangiferin produces more stable interaction with WT1 compared to neomangiferin, suggesting its improved inhibitory potential due to more reliable binding.

Kata Kunci : HCC, mangiferin, molecular docking, molecular dynamics, Wnt/?-catenin pathway