Sharma_2020_J.Biomol.Struct.Dyn_38_5349

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 (MM/GBSA) 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 (MD) 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: 6.2microM. Compound MolMall-20062 could be taken as a good lead for the development of DPP-IV inhibitors.Abbreviations: ADME: Absorption, Distribution, Metabolism and Excretion; ChEBI: Chemical Entities of Biological Interest; DPP-IV: Dipeptidyl peptidase IV; DISCOtech: Distance Comparisons; HTVS: High Throughput Virtual Screening; MD: Molecular Dynamics; MM-GBSA: Molecular Mechanics-Generalized Born Surface Area; OGTT: Oral Glucose Tolerance Test; PBVS: Pharmacophore Based Virtual Screening; PDB: Protein Data Bank; RMSD: Root Mean Square Deviation; ROC: Receiver Operating Characteristics; SP: Standard Precision; SBVS: Structure Based Virtual Screening; VS: Virtual Screening; XP: Extra Precision.