In silico fragment-based discovery of DPP-IV S1 pocket binders

A virtual screening approach for S1-binding fragments of dipeptidyl peptidase IV using FlexX-Pharm docking confirmed substructures of known inhibitors and identified novel fragments with activities in the micromolar range suitable as starting points for structure-based design. Dipeptidyl peptidase IV is a clinically validated target for type-2 diabetes and belongs to a family of peptidases with a quite unique post-proline cleavage specificity. Known inhibitors contain a limited number of molecular anchors occupying the small prototypical S1 pocket. A virtual screening approach for such S1-binding fragments was carried out using FlexX docking to evaluate its potential to confirm known and find novel compounds. Several low molecular weight inhibitors exhibiting activities in the micromolar range could be identified as starting points for structure-based design.