Structure-based virtual screening approach to identify novel classes of PTP1B inhibitors.

Discovery of protein tyrosine phosphatase 1B (PTP1B) inhibitors has been actively pursued with the aim to develop therapeutics for the treatment of type 2 diabetes and obesity. We have been able to identify 9 novel PTP1B inhibitors by means of a computer-aided drug design protocol involving virtual screening with docking simulations under consideration of the effects of ligand solvation in the binding free energy function. Because the newly discovered inhibitors are structurally diverse and reveal a significant potency with IC(50) values lower than 50 microM, all of them can be considered for further development by structure-activity relationship studies. Structural features relevant to the interactions of the newly identified inhibitors with the active-site residues of PTP1B are discussed in detail.