Mining of potential dipeptidyl peptidase-IV inhibitors as anti-diabetic agents using integrated in silico approaches

J Biomol Struct Dyn. 2020 Nov;38(18):5349-5361. doi: 10.1080/07391102.2019.1701553. Epub 2019 Dec 18.


The dipeptidyl peptidase-IV (DPP-IV) family of receptors possesses a large binding cavity that imparts promiscuity for number of ligand binding which is not common to other receptors. This feature increases the challenge of using computational methods to identify DPP-IV inhibitors, therefore using both pharmacophore and structure-based screening seems to be a reliable approach. Mining of novel DPP-IV inhibitors by integrating both of these in silico techniques was reported. Pharmacophore model (Model_008) obtained from structurally diverse reported compounds was used as a template for screening of MolMall database followed by structure-based screening against PDB ID: 5T4E. After absorption, distribution, metabolism and excretion (ADME) analysis of shortlisted compounds, consensus docking and molecular mechanics/generalized born surface area studies were carried out. The results of the docking studies obtained were comparable to that of the reference ligand. Out of nine hits identified, only one hit (ID MolMall-20062) was available which was procured through exchange program. Molecular dynamic simulation studies of the procured hit revealed its good selectivity and stability in DPP-IV binding pocket and interactions observed with important amino acids viz., Trp629, Lys544 and Arg125. Biological testing of the compound MolMall-20062 showed promising DPP-IV inhibition activity with IC50: 6.2 µM. Compound MolMall-20062 could be taken as a good lead for the development of DPP-IV inhibitors.AbbreviationsADMEabsorption, distribution, metabolism and excretionChEBIchemical entities of biological interestDPP-IVdipeptidyl peptidase IVDISCOtechdistance comparisonsHTVShigh throughput virtual screeningMDmolecular dynamicsMM-GBSAmolecular mechanics-generalized born surface areaOGTToral glucose tolerance testPBVSpharmacophore-based virtual screeningPDBprotein data bankRMSDroot mean square deviationROCreceiver operating characteristicsSPstandard precisionSBVSstructure-based virtual screeningVSvirtual screeningXPextra precisionCommunicated by Ramaswamy H. Sarma.

Keywords: ADME; Dipeptidyl peptidase-IV; PBVS; molecular dynamics; pharmacophore mapping; virtual screening.

MeSH terms

  • Computer Simulation
  • Diabetes Mellitus / drug therapy
  • Dipeptidyl-Peptidase IV Inhibitors* / pharmacology
  • Hypoglycemic Agents* / pharmacology
  • Ligands
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation
  • Molecular Structure


  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • Ligands