Issue 5, 2024

Structure-based virtual screening of unbiased and RNA-focused libraries to identify new ligands for the HCV IRES model system

Abstract

Targeting RNA including viral RNAs with small molecules is an emerging field. The hepatitis C virus internal ribosome entry site (HCV IRES) is a potential target for translation inhibitor development to raise drug resistance mutation preparedness. Using RNA-focused and unbiased molecule libraries, a structure-based virtual screening (VS) by molecular docking and pharmacophore analysis was performed against the HCV IRES subdomain IIa. VS hits were validated by a microscale thermophoresis (MST) binding assay and a Förster resonance energy transfer (FRET) assay elucidating ligand-induced conformational changes. Ten hit molecules were identified with potencies in the high to medium micromolar range proving the suitability of structure-based virtual screenings against RNA-targets. Hit compounds from a 2-guanidino-quinazoline series, like the strongest binder, compound 8b with an EC50 of 61 μM, show low molecular weight, moderate lipophilicity and reduced basicity compared to previously reported IRES ligands. Therefore, it can be considered as a potential starting point for further optimization by chemical derivatization.

Graphical abstract: Structure-based virtual screening of unbiased and RNA-focused libraries to identify new ligands for the HCV IRES model system

Supplementary files

Article information

Article type
Research Article
Submitted
08 12 2023
Accepted
16 3 2024
First published
18 3 2024
This article is Open Access
Creative Commons BY license

RSC Med. Chem., 2024,15, 1527-1538

Structure-based virtual screening of unbiased and RNA-focused libraries to identify new ligands for the HCV IRES model system

E. Kallert, L. Almena Rodriguez, J. Husmann, K. Blatt and C. Kersten, RSC Med. Chem., 2024, 15, 1527 DOI: 10.1039/D3MD00696D

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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