Study of Interaction between HBx Protein Model and Non-Nucleoside Agents for Hepatitis B by in silico method

• Main Author: Almira, Gaby
• Format: Final Project
• Language: Indonesia
• Subjects: Kimia
• Online Access: https://digilib.itb.ac.id/gdl/view/32219
• Institution: Institut Teknologi Bandung

Hepatitis B is a viral infection which can cause liver chirrosis and liver cancer, and is considered as a global health problem. Hepatitis B drug therapies approved by FDA have problems with developed viral resistence after long-term using. One of new target alternatives is HBx protein which has many roles in key biological processes in hepatitis B virus. In this study, 3D structure of HBx was determined by ab initio method with QUARK algorithm. The resulted structure was refined further by 20 ns molecular dynamics (MD) simulation using Amber 12 program and was validated using ProCheck program. In the course of MD simulation, some conformational transitions of the protein were occurred particularly at the secondary structural level due to the energetic adaptation toward the lowest energy conformation. Among the structures resulted by conformational transitions during 20 ns simulation, the structure formed at 19 ns simulation was likely the best one. This structure was then selected as the receptor for molecular docking with Autodock Vina program. All ligands used in this study were constructed from the well-known non-nucleoside agents for Hepatitis B drug therapy. Among 23 constructed ligands, there was only one ligand, namely substituted tetrahydro-tetrazolo-pyrimidine, whose binding energy reached -9.8 kcal/mol and had spesific interactions with the receptor. This ligand structure was modified to further stabilize the binding interactions with the receptor. Modification with hydroxyl group was succesfully stabilize its interactions with the receptor, as revealed by the lower value of binding energy i.e. -10.3 kcal/mol. The docking interaction was verified with 5 ns MD simulation. Protein-ligand complex structure changed as a result of conformational adaptation in both protein and ligand. The resulted complex structure at 5 ns simulation was re-docked to calculate new binding configuration and it was found that the free binding energy changed into -9.2 kcal/mol. The lowering binding stability was caused by the decreasing number of hydrogen bond in the new binding configuration. Although there was slight decreasing in binding stability, our study suggests that the modified version of substituted tetrahydro-tetrazolo-pyrimidine can bind well to HBx protein model, and is potential to be further developed as a novel Hepatitis B drug.