Target-based Design, Structural Optimization and Characterization of Novel Hepatitis B Virus Capsid Assembly Modulators

Identifier:  TDX:3196

Handle: https://hdl.handle.net/20.500.11797/TDX3196

Authors:  Detta, Elena

Abstract:
Chronic hepatitis B is a severe liver infection caused by Hepatitis B Virus (HBV). Despite the availability of a prophylactic vaccination since 1982, HBV infection still remains a serious global health issue with more than 250 million carriers worldwide. Currently, HBV infection is treated with nucleos(t)ide analogs (NUCs) and, less commonly, interferon-based therapy (IFN-α). However, the standard of care (SOC) does not provide a functional cure. Thus, there is a significant need for novel therapeutics aiming towards the complete eradication of the virus from infected hepatocytes. Small-molecule capsid assembly modulators (CAMs) have been recently recognized as promising antiviral agents for curing chronic HBV infection. The VIRO-FLOW project aims at the fast and efficient identification of novel curative agents for HBV, integrating the advantages of continuous flow chemistry with in vitro microfluidic bioassay technologies. The end objective of the present thesis project was the creation of an integrated system for the generation of structure-activity relationship (SAR) data, where a suite of computational techniques could be utilized to speed up the process of hit/lead identification, to optimize out undesirable pharmacological properties of known actives and to guide and support the synthesis of compound libraries either in batch or flow. State of the art computer-aided design approaches, including virtual screening, scaffold hopping, in silico focussed library design and molecular docking studies of potential active compounds, adopted in this research work led to the identification of novel libraries of HBV CAMs. Moreover, an efficient method for the synthesis of the [1,2,4]triazolo[1,5-a]pyridine-2-carboxamide scaffold was also developed in continuous flow with the aid of DFT calculations to elucidate the mechanism of the process.