PhAST: pharmacophore alignment search tool.
We present a ligand-based virtual screening technique (PhAST) for rapid hit and lead structure searching in large compound databases. Molecules are represented as strings encoding the distribution of pharmacophoric features on the molecular graph. In contrast to other text-based methods using SMILES strings, we introduce a new form of text representation that describes the pharmacophore of molecules. This string representation opens the opportunity for revealing functional similarity between molecules by sequence alignment techniques in analogy to homology searching in protein or nucleic acid sequence databases. We favorably compared PhAST with other current ligand-based virtual screening methods in a retrospective analysis using the BEDROC metric. In a prospective application, PhAST identified two novel inhibitors of 5-lipoxygenase product formation with minimal experimental effort. This outcome demonstrates the applicability of PhAST to drug discovery projects and provides an innovative concept of sequence-based compound screening with substantial scaffold hopping potential.
Hähnke
Volker
V
Institute of Organic Chemistry and Chemical Biology/ZAFES, Goethe-University Frankfurt am Main, Siesmayerstr. 70, D-60323 Frankfurt am Main, Germany.
Hofmann
Bettina
B
Grgat
Tomislav
T
Proschak
Ewgenij
E
Steinhilber
Dieter
D
Schneider
Gisbert
G
D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry; D008024:Ligands; D016859:Lipoxygenase Inhibitors; D011446:Prospective Studies; D012189:Retrospective Studies; D016415:Sequence Alignment / Q000379:methods*; D054852:Small Molecule Libraries
D004791:Enzyme Inhibitors; D008024:Ligands; D016859:Lipoxygenase Inhibitors; D054852:Small Molecule Libraries