A pseudo-ligand approach to virtual screening.
A virtual screening method is presented that is grounded on a receptor-derived pharmacophore model termed "virtual ligand" or "pseudo-ligand". The model represents an idealized constellation of potential ligand sites that interact with residues of the binding pocket. For rapid virtual screening of compound libraries the potential pharmacophore points of the virtual ligand are encoded as an alignment-free correlation vector, avoiding spatial alignment of pharmacophore features between the pharmacophore query (i.e., the virtual ligand) and the candidate molecule. The method was successfully applied to retrieving factor Xa inhibitors from a Ugi three-component combinatorial library, and yielded high enrichment of actives in a retrospective search for cyclooxygenase-2 (COX-2) inhibitors. The approach provides a concept for "de-orphanizing" potential drug targets and identifying ligands for hitherto unexplored or allosteric binding pockets.
Schüller
Andreas
A
Johann Wolfgang Goethe-Universität, Institut für Organische Chemie und Chemische Biologie, Siesmayerstr. 70, D-60323 Frankfurt am Main, Germany.
Fechner
Uli
U
Renner
Steffen
S
Franke
Lutz
L
Weber
Lutz
L
Schneider
Gisbert
G
D000990:Antithrombin III / Q000494:pharmacology; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D019295:Computational Biology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D016208:Databases, Factual; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008024:Ligands; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship
D052246:Cyclooxygenase 2 Inhibitors; D008024:Ligands; D015842:Serine Proteinase Inhibitors; D000990:Antithrombin III