Discovery of novel aminomethyl-piperidone derivatives as dipeptidyl peptidase-4 inhibitors

DPP-IV inhibitors known as oral antidiabetic drugs manage type 2 diabetes by preventing the breakdown of incretin hormones, which help regulate blood sugar. The current study displayed the effectiveness of aminomethyl-piperidone derivatives as an antidiabetic agent. This study aimed to investigate the antidiabetic potential of aminomethyl-piperidone derivatives through computational approaches and to identify promising novel DPP-IV inhibitors. A total of 32 ligands were used in pharmacophore modelling, 3D-QSAR analysis, virtual screening, molecular docking, MD simulations and ADME prediction. The HHPRR_1 pharmacophore model exhibited the highest survival score (5.73). The 3D-QSAR study demonstrated the significant model with R 2 = 0.9439 and Q 2 = 0.8405. Among these series the top scoring compound was 13e showed good binding interactions with receptor. The pharmacophore model was used to screen the ZINC compounds where ZINC57775421 displayed the best binding interactions with the amino acid residues Tyr666, Arg125, Tyr547 and Trp629 (PDB ID: 2OQI). The enumeration study screened compounds P1 and P2 with binding scores −9.302 and −8.202. The MD simulations (100 ns) further verified that all of the interactions of DPP-4 complexes are stable. The RMSD value stabilized within a range of 1.5–2.5 Å where the reference ligand and ZINC57775421 exhibit the least deviation which represents very high stability. The RMSF analysis has shown the residue flexibility being at less than 1.8 Å confirming the stable receptor-ligand interactions. The results of this investigation might be helpful in the future development of methyl piperidone derivatives as DPP4 inhibitors.