In recent years, various dipeptidyl peptidase IV (DPP-4) inhibitors have been 
released as therapeutic drugs for type 2 diabetes in many countries. In spite of 
their diverse chemical structures, no comparative studies of their binding modes 
in the active site of DPP-4 have been disclosed. We determined the co-crystal 
structure of vildagliptin with DPP-4 by X-ray crystallography and compared the 
binding modes of six launched inhibitors in DPP-4. The inhibitors were 
categorized into three classes on the basis of their binding subsites: (i) 
vildagliptin and saxagliptin (Class 1) form interactions with the core S1 and S2 
subsites and a covalent bond with Ser630 in the catalytic triad; (ii) alogliptin 
and linagliptin (Class 2) form interactions with the S1' and/or S2' subsites in 
addition to the S1 and S2 subsites; and (iii) sitagliptin and teneligliptin 
(Class 3) form interactions with the S1, S2 and S2 extensive subsites. The 
present study revealed that the additional interactions with the S1', S2' or S2 
extensive subsite may increase DPP-4 inhibition beyond the level afforded by the 
fundamental interactions with the S1 and S2 subsites and are more effective than 
forming a covalent bond with Ser630.