Identification of Novel HBV/HDV Entry Inhibitors by Pharmacophore- and QSAR-Guided Virtual Screening

Viruses

Sami Alakurtti¹  Jari Yli-Kauhaluoma¹  Reimar Krieg²  Felix Lehmann³  Nora Goldmann³  Dieter Glebe³  Kira Alessandra Alicia Theresa Lowjaga⁴  Joachim Geyer⁴  Michael Kirstgen⁴  Simon Franz Müller⁴  Karl-Heinz Baringhaus⁵ 

[1] Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, FI-00014 Helsinki, Finland;Institute of Anatomy II, University Hospital Jena, Teichgraben 7, 07743 Jena, Germany;Institute of Medical Virology, National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, Justus Liebig University Giessen, 35392 Giessen, Germany;Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany;Sanofi-Aventis Deutschland GmbH, 65926 Frankfurt, Germany;

关键词: HBV;    HDV;    NTCP;    entry inhibitor;    QSAR;    pharmacophore;   

DOI  :  10.3390/v13081489

来源: DOAJ

【 摘 要 】

The hepatic bile acid transporter Na⁺/taurocholate co-transporting polypeptide (NTCP) was identified in 2012 as the high-affinity hepatic receptor for the hepatitis B and D viruses (HBV/HDV). Since then, this carrier has emerged as promising drug target for HBV/HDV virus entry inhibitors, but the synthetic peptide Hepcludex^® of high molecular weight is the only approved HDV entry inhibitor so far. The present study aimed to identify small molecules as novel NTCP inhibitors with anti-viral activity. A ligand-based bioinformatic approach was used to generate and validate appropriate pharmacophore and QSAR (quantitative structure–activity relationship) models. Half-maximal inhibitory concentrations (IC₅₀) for binding inhibition of the HBV/HDV-derived preS1 peptide (as surrogate parameter for virus binding to NTCP) were determined in NTCP-expressing HEK293 cells for 150 compounds of different chemical classes. IC₅₀ values ranged from 2 µM up to >1000 µM. The generated pharmacophore and QSAR models were used for virtual screening of drug-like chemicals from the ZINC¹⁵ database (~11 million compounds). The 20 best-performing compounds were then experimentally tested for preS1-peptide binding inhibition in NTCP-HEK293 cells. Among them, four compounds were active and revealed experimental IC₅₀ values for preS1-peptide binding inhibition of 9, 19, 20, and 35 µM, which were comparable to the QSAR-based predictions. All these compounds also significantly inhibited in vitro HDV infection of NTCP-HepG2 cells, without showing any cytotoxicity. The best-performing compound in all assays was ZINC000253533654. In conclusion, the present study demonstrates that virtual compound screening based on NTCP-specific pharmacophore and QSAR models can predict novel active hit compounds for the development of HBV/HDV entry inhibitors.

【 授权许可】

Unknown