title: Ligand Optimization by Improving Shape Complementarity at a Hepatitis C Virus RNA Target.
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.
authors: Department of Chemistry and Biochemistry, University of California , San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
authors: Brian P
authors: BP
authors: Charrette
authors: Department of Chemistry and Biochemistry, University of California , San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
authors: Mark A
authors: MA
authors: Boerneke
authors: Department of Chemistry and Biochemistry, University of California , San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.|Center for Drug Discovery Innovation, University of California , San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
authors: Thomas
authors: T
authors: Hermann
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D016174:Hepacivirus / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D000067556:Internal Ribosome Entry Sites / Q000187:drug effects*; D008024:Ligands; D008958:Models, Molecular; D009690:Nucleic Acid Conformation / Q000187:drug effects; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D012367:RNA, Viral / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D000067556:Internal Ribosome Entry Sites; D008024:Ligands; D011799:Quinazolines; D012367:RNA, Viral; C031000:benzimidazole