Structure-based discovery of new small molecule inhibitors of low molecular weight protein tyrosine phosphatase.
The application of a fully integrated and automated virtual screening method for identifying potential and novel inhibitors of bovine lmwPTP is described. The protocol makes extensive use of our recently introduced LINGO tools, which allow the extraction of the implicit chemical information present in SMILES representations. Nine out of 34 compounds selected from a database of almost 500,000 commercially available compounds were experimentally confirmed to be competitive inhibitors of lmwPTP, two of them showing K(i) values around 10microM. The best inhibitors previously described had K(i) values higher than 1mM. These results constitute an experimental validation of our virtual screening algorithm and provide a basis for the optimization of pharmacologically interesting lmwPTP inhibitors.
Vidal
David
D
Laboratory of Biomolecular NMR, Institute for Research in Biomedicine (IRB), Barcelona Science Park, Josep Samitier 1-5, 08028 Barcelona, Spain.
Blobel
Jascha
J
Pérez
Yolanda
Y
Thormann
Michael
M
Pons
Miquel
M
D000465:Algorithms; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008970:Molecular Weight; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D017027:Protein Tyrosine Phosphatases