1. Ligand Optimization by Improving Shape Complementarity at a Hepatitis C Virus RNA Target.
- Author
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Charrette BP, Boerneke MA, and Hermann T
- Subjects
- Antiviral Agents chemistry, Benzimidazoles chemistry, Drug Design, Hepacivirus chemistry, Hepacivirus metabolism, Hepatitis C drug therapy, Hepatitis C virology, Humans, Ligands, Models, Molecular, Nucleic Acid Conformation drug effects, Quinazolines chemistry, RNA, Viral chemistry, Antiviral Agents pharmacology, Benzimidazoles pharmacology, Hepacivirus drug effects, Internal Ribosome Entry Sites drug effects, Quinazolines pharmacology, RNA, Viral metabolism
- Abstract
Crystal structure analysis revealed key interactions of a 2-amino-benzimidazole viral translation inhibitor that captures an elongated conformation of an RNA switch target in the internal ribosome entry site (IRES) of hepatitis C virus (HCV). Here, we have designed and synthesized quinazoline derivatives with improved shape complementarity at the ligand binding site of the viral RNA target. A spiro-cyclopropyl modification aimed at filling a pocket in the back of the RNA binding site led to a 5-fold increase of ligand affinity while a slightly more voluminous dimethyl substitution at the same position did not improve binding. We demonstrate that precise shape complementarity based solely on hydrophobic interactions contributes significantly to ligand binding even at a hydrophilic RNA target site such as the HCV IRES conformational switch.
- Published
- 2016
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