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New Inhibitors of the Tat–TAR RNA Interaction Found with a “Fuzzy” Pharmacophore Model
Author(s) -
Renner Steffen,
Ludwig Verena,
Boden Oliver,
Scheffer Ute,
Göbel Michael,
Schneider Gisbert
Publication year - 2005
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200400376
Subject(s) - pharmacophore , virtual screening , rna , small molecule , tar (computing) , förster resonance energy transfer , chemistry , computational biology , combinatorial chemistry , ligand (biochemistry) , molecule , biophysics , fluorescence , stereochemistry , biochemistry , computer science , biology , receptor , physics , organic chemistry , gene , programming language , quantum mechanics
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 (IC 50 =46 μ M ). The hits had molecular scaffolds different from those of the reference molecules.