Mining of potential dipeptidyl peptidase-IV inhibitors as anti-diabetic agents using integrated <i>in silico</i> approaches
Creators: name: Sharma, Shweta
name: Shubham Srivastava
name: Apeksha Shrivastava
name: Malik, Ruchi
name: Almalki, Faisal
name: Saifullah, Khalid
name: Alam, Mohammad Mumtaz
name: Shaqiquzzaman, Mohammad
name: Ali, Shakir
name: Mymoona Akhter
Publisher: name: Taylor & Francis
Year: 2019
Subjects: subject: Biophysics
subject: Biochemistry
subject: Genetics
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Molecular Biology
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: 80699 Information Systems not elsewhere classified
subject: FOS: Computer and information sciences
subject: FOS: Computer and information sciences
subject: 110309 Infectious Diseases
subject: FOS: Health sciences
subject: FOS: Health sciences
subject: Computational Biology

description: 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 <i>in silico</i> 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 (<b>ID MolMall-20062</b>) 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 <b>MolMall-20062</b> showed promising DPP-IV inhibition activity with IC<sub>50</sub>: 6.2 µM. Compound <b>MolMall-20062</b> 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 precision absorption, distribution, metabolism and excretion chemical entities of biological interest dipeptidyl peptidase IV distance comparisons high throughput virtual screening molecular dynamics molecular mechanics‐generalized born surface area oral glucose tolerance test pharmacophore-based virtual screening protein data bank root mean square deviation receiver operating characteristics standard precision structure-based virtual screening virtual screening extra precision Communicated by Ramaswamy H. Sarma