Synthesis, in vitro evaluation, and computational simulations studies of 1,2,3-triazole analogues as DPP-4 inhibitors

Duy Viet Vo, Kwon Ho Hong, Jongkook Lee, Haeil Park

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Novel 1,2,3-triazole analogues (S7 ~ S10) were synthesized and evaluated for their inhibitory activity against hDPP-4. All the 1,2,3-triazole analogues exhibited moderate in vitro hDPP-4 inhibitory activities (265 ~ 780 nM). These results are somewhat less potent compared to those of known 1,2,3-triazole analogues (S1 ~ S6, 14 ~ 254 nM). S2 and S3 manifested excellent potency against hDPP-4 with IC50s of 28 and 14 nM, respectively. The role of the 1,2,3-triazole moiety in binding the molecule to the target was investigated using combined 10 1,2,3-triazole analogues (S1 ~ S10). Molecular dynamics (MD) simulations following the aforementioned docking phase were performed to elucidate potential binding modes of sitagliptin's 1,2,3-triazole analogues in hDPP-4, with the use of a cocrystal structure of hDPP-4 with sitagliptin (PDB ID: 1X70). Docking and MD simulations of the complexes of hDPP-4 with sitagliptin, S2 and S3 suggest that Glu205, Glu206, Tyr662, and Tyr666 would be the key amino acid residues for the binding of the molecules with the receptor. Especially, S2 and S3 showed additional strong π-π interaction between Phe357 and 1,2,3-triazole. Same strong π-π interaction is also observed between Phe357 and the 1,2,4-triazole ring of sitagliptin. Furthermore, additional interactions with Tyr547, Cys551, and especially Arg358 would enhance the binding affinity of the compounds for the pocket of the enzyme. In overall, in vitro hDPP-4 inhibitory activities of synthetic 1,2,3-triazole analogues were well matched with results of computational simulations studies.

Original languageEnglish (US)
Article number115861
JournalBioorganic and Medicinal Chemistry
StatePublished - Jan 1 2021

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea ( NRF-2016-R1D1A1B03934926 : Development of Antidiabetic Agents with DPP-4 Inhibitory Activity). The authors thank to Drug Development Research Institute and Central Laboratory of Kangwon National University for the use of analytical instruments and bioassay facilities.

Publisher Copyright:
© 2020 Elsevier Ltd


  • 1,2,3-triazole analogues
  • Antidiabetic drugs
  • Computational simulations
  • DPP-4 inhibitors
  • Docking
  • MD simulations
  • Sitagliptin

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't


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