Comparative Binding Analysis of Dipeptidyl Peptidase IV (DPP-4) with Antidiabetic Drugs - An Ab Initio Fragment Molecular Orbital Study.
Dipeptidyl peptidase IV (DPP-4) enzyme is responsible for the degradation of incretins that stimulates insulin secretion and hence inhibition of DPP-4 becomes an established approach for the treatment of type 2 diabetics. We studied the interaction between DPP-4 and its inhibitor drugs (sitagliptin 1, linagliptin 2, alogliptin 3, and teneligliptin 4) quantitatively by using fragment molecular orbital calculations at the RI-MP2/cc-pVDZ level to analyze the inhibitory activities of the drugs. Apart from having common interactions with key residues, inhibitors encompassing the DPP-4 active site extensively interact widely with the hydrophobic pocket by their hydrophobic inhibitor moieties. The cumulative hydrophobic interaction becomes stronger for these inhibitors and hence linagliptin and teneligliptin have larger interaction energies, and consequently higher inhibitory activities, than their alogliptin and sitagliptin counterparts. Though effective interaction for both 2 and 3 is at [Formula: see text] subsite, 2 has a stronger binding to this subsite interacting with Trp629 and Tyr547 than 3 does. The presence of triazolopiperazine and piperazine moiety in 1 and 4, respectively, provides the interaction to the S2 extensive subsite; however, the latter's superior inhibitory activity is not only due to a relatively tighter binding to the S2 extensive subsite, but also due to the interactions to the S1 subsite. The calculated hydrophobic interfragment interaction energies correlate well with the experimental binding affinities (KD) and inhibitory activities (IC50) of the DPP-4 inhibitors.
Department of Chemistry, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.|Research Center for Smart molecules, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.
Sundaram
S
Arulmozhiraja
Department of Chemistry, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.
Naoya
N
Matsuo
Department of Chemistry, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.
Erika
E
Ishitsubo
Department of Chemistry, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.|Research Center for Smart molecules, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.
Seiji
S
Okazaki
Department of Internal Medicine (Endocrinology and Metabolism), University of Tsukuba, Tsukuba 305-8575, Japan.|AMED-CREST, Tokyo, Japan.
Hitoshi
H
Shimano
Department of Chemistry, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.|Research Center for Smart molecules, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.|AMED-CREST, Tokyo, Japan.
Hiroaki
http://orcid.org/0000-0002-3790-1799
H
Tokiwa
D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D000069476:Linagliptin / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D000068900:Sitagliptin Phosphate / Q000737:chemistry / Q000494:pharmacology*; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology*; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
C579035:3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D010880:Piperidines; D011720:Pyrazoles; D053778:Thiazolidines; D000069476:Linagliptin; D014498:Uracil; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; C520853:alogliptin; D000068900:Sitagliptin Phosphate