Discovery of New Small Molecule Hits as Hepatitis B Virus Capsid Assembly Modulators: Structure and Pharmacophore-Based Approaches

• Type of Material: Article
• Authors: Sameera Senaweera, University of Minnesota, Minneapolis; Haijuan Du, Emory University; Huanchun Zhang, Emory University; Karen Kirby, Emory University; Philip Tedbury, Emory University; Jiashu Xie, University of Minnesota, Minneapolis; Stefan Sarafianos, Emory University; Zhengqiang Wang, University of Minnesota, Minneapolis
• Language: English
• Date: 2021-05-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2021 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/v13050770
• Title of Journal or Parent Work: VIRUSES-BASEL
• Volume: 13
• Issue: 5
• Grant/Funding Information: This research was funded by the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH), grant number R01AI121315 (to S.G.S. and Z.W.). S.G.S. acknowledges funding from the Nahmias-Schinazi Distinguished Chair in Research.
• Keywords: GLIDE; Virology; virtual screening; REPLICATION; Hepatitis B virus; PHASE; Science & Technology; capsid assembly modulators; DERIVATIVES; protein-protein interaction; CORE PROTEIN; ACCURATE DOCKING; BIOLOGICAL EVALUATION; DATABASE; Life Sciences & Biomedicine; DESIGN; pharmacophore modelling; METHODOLOGY
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Pharmacy

Abstract

Hepatitis B virus (HBV) capsid assembly modulators (CpAMs) have shown promise as potent anti-HBV agents in both preclinical and clinical studies. Herein, we report our efforts in identifying novel CpAM hits via a structure-based virtual screening against a small molecule protein-protein interaction (PPI) library, and pharmacophore-guided compound design and synthesis. Curated compounds were first assessed in a thermal shift assay (TSA), and the TSA hits were further evaluated in an antiviral assay. These efforts led to the discovery of two structurally distinct scaffolds, ZW-1841 and ZW-1847, as novel HBV CpAM hits, both inhibiting HBV in single-digit µM concentrations without cytotoxicity at 100 µM. In ADME assays, both hits displayed extraordinary plasma and microsomal stability. Molecular modeling suggests that these hits bind to the Cp dimer interfaces in a mode well aligned with known CpAMs.