title: New inhibitors of the Tat-TAR RNA interaction found with a "fuzzy" pharmacophore model.
abstract: TAR RNA is a potential target for AIDS therapy. Ligand-based virtual screening was performed to retrieve novel scaffolds for RNA-binding molecules capable of inhibiting the Tat-TAR interaction, which is essential for HIV replication. We used a "fuzzy" pharmacophore approach (SQUID) and an alignment-free pharmacophore method (CATS3D) to carry out virtual screening of a vendor database of small molecules and to perform "scaffold-hopping". A small subset of 19 candidate molecules were experimentally tested for TAR RNA binding in a fluorescence resonance energy transfer (FRET) assay. Both methods retrieved molecules that exhibited activities comparable to those of the reference molecules acetylpromazine and chlorpromazine, with the best molecule showing ten times better binding behavior (IC50 = 46 microM). The hits had molecular scaffolds different from those of the reference molecules.
authors.affiliation: Beilstein Endowed Chair for Cheminformatics, Institut für Organische Chemie und Chemische Biologie, Johann-Wolfgang-Goethe-Universität, Marie-Curie-Strasse 11, 60439 Frankfurt am Main, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Renner
authors.forename: Verena
authors.initials: V
authors.lastname: Ludwig
authors.forename: Oliver
authors.initials: O
authors.lastname: Boden
authors.forename: Ute
authors.initials: U
authors.lastname: Scheffer
authors.forename: Michael
authors.initials: M
authors.lastname: Göbel
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000075:Acepromazine / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002746:Chlorpromazine / Q000494:pharmacology; D015195:Drug Design; D031541:Fluorescence Resonance Energy Transfer; D015696:Gene Products, tat / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry / Q000378:metabolism; D009690:Nucleic Acid Conformation; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D019380:Anti-HIV Agents; D015696:Gene Products, tat; D012367:RNA, Viral; D054322:tat Gene Products, Human Immunodeficiency Virus; D000075:Acepromazine; D002746:Chlorpromazine