ANALYSIS OF CRYSTAL STRUCTURES OF DIPEPTIDYL PEPTIDASE 4 (DPP 4) CO-CRYSTALLIZED WITH DIVERSE INHIBITORS

Crystal structures of target are an indispensible tool in modern methods of rational drug design and discovery. Hence, judicious selection of crystal structures for virtual screening and ligand docking is essential. In recent times, a number of new chemical entities (NCEs) have been introduced into the drug discovery pipeline with these methods in treatment of type 2 diabetes. Dipeptidyl peptidase 4 (DPP 4) enzyme splits an incretin based glucoregulatory hormone glucagon like peptide -1(GLP-1) from N-terminal of peptide, where penultimate amino acid is either alanine or proline. Several DPP 4 inhibitors, “gliptins”, are approved for management of type 2 diabetes or are under clinical trials. Crystal structures of DPP 4 have been released by various research groups that may assist rapid discovery of new DPP 4 inhibitors. 18 crystal structures of DPP 4 bound to various inhibitors are analyzed in the present work to gain insight into interactions between the protein and ligands. Chemically all DPP 4 inhibitors are diverse in nature but occupy same binding site. Key amino acid residues essential for optimum interaction between protein and ligands are discussed with emphasis on orientation of ligand in active site of DPP 4.