BioE PhD Proposal Presentation- Zixing Fan

Advisors:

Dr. James C Gumbart (School of Physics)

Committee:

Dr. M. G. Finn (School of Chemistry & Biochemistry), Dr. Peter Kasson (School of Chemistry & Biochemistry), Dr. Jeffrey Skolnick (School of Biological Sciences), Dr. Adegboyega Oyelere (School of Chemistry & Biochemistry)

Altering Hepatitis B Virus Capsid Assembly through Pharmacological Intervention

Chronic hepatitis B virus (HBV) infection affects approximately 250 million people globally, leading to around 800,000 deaths annually from liver-related complications. This thesis focuses on disrupting HBV capsid assembly, a critical step in the viral life cycle, through pharmacological intervention, with the aim of advancing antiviral drug discovery. The research is structured around three key objectives. The first objective is to discover and optimize novel capsid assembly modulators (CAMs) using computational methods, including molecular docking and molecular dynamics simulations. This approach will identify compounds that interfere with HBV capsid assembly, followed by optimization to enhance their efficacy and drug-like properties. The second objective involves fragment-based drug design to explore the interactions of small molecular fragments with a novel binding site, distinct from the conventional CAM binding pocket. This will guide the design of larger drug molecules, opening up new avenues for targeting HBV life cycle. The third objective investigates how small molecules allosterically alter the viral assembly pathway. By employing computational techniques such as the string method and free energy calculations, this aim will explore the conformational changes and energy barriers associated with capsid formation, providing mechanistic insights that could inform future antiviral strategies. Through the integration of drug discovery, compound optimization, and mechanistic analysis, this research aims to contribute to the development of novel therapeutic agents for HBV, offering potential new treatments for viral infection.