title: A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site.
abstract: 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.
authors.affiliation: Medicinal Chemistry Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan. nabeno.mika@mv.mt-pharma.co.jp
authors.forename: Mika
authors.initials: M
authors.lastname: Nabeno
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Akahoshi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishida
authors.forename: Ikuko
authors.initials: I
authors.lastname: Miyaguchi
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ishii
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry*; D006801:Humans; D046912:Multiprotein Complexes / Q000032:analysis / Q000737:chemistry; D009570:Nitriles / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011719:Pyrazines / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry*; D012694:Serine / Q000737:chemistry; D000068900:Sitagliptin Phosphate; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry; D014498:Uracil / Q000031:analogs & derivatives / Q000737:chemistry; D000077597:Vildagliptin; D014961:X-Ray Diffraction
chemical_list: C579035:3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D046912:Multiprotein Complexes; D009570:Nitriles; D009842:Oligopeptides; D010880:Piperidines; D011719:Pyrazines; D011720:Pyrazoles; D011759:Pyrrolidines; D053778:Thiazolidines; D014230:Triazoles; D012694:Serine; D014498:Uracil; C041445:diprotin A; C502994:saxagliptin; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; C520853:alogliptin; D000218:Adamantane; D000068900:Sitagliptin Phosphate