Synthesis, Molecular Docking And In Silico Drug-likeness Evaluation Of Substituted Pyrrolidine-2-carbonitrile Derivatives

Aim Diabetes is an increasing chronic, metabolic disease that millions of people are suffering from. The incretin hormone, glucagon-like peptide-1(GLP-1) is a kind of peptide intestinal insulin which can control blood-sugar levels by several biochemical pathways. But, the endogenous and exogenous peptides GLP-1 is instability in the body, and active GLP-1 is rapidly degraded to the inactive by dipeptidyl peptidase-4(DPP-4). Based on the physiological effect of GLP-1, we take the DPP-4 as the research target, and draw on the experience of the skeleton activity relationship of DPP-4 inhibitors. Our extraordinary efforts were made to improve the stability and the long-acting potential of conventional DPP-4 inhibitors.Methods Several compounds classes of DPP-4 inhibitors are known, the most prominent being cyanopyrrolidines. But the chemical stability of this class of compounds is poor. In order to improve the chemical stability of inhibitors, a serial of(S)-1-(2-(disubstituted-methylamino)acetyl)pyrrolidine-2-carbonitrile derivatives were designed by fragment based drug discovery(FBDD), using the active effective fragment disubstituted methylamino to replaced the adamantine of lead compound LAF-237 based on the principle of skeleton substitution. And the DPP-4 inhibitory activity was evaluated via virtual screening using molecular docking program, the drug-likeness was evaluated via the online drug-likeness forecast. LAF-237 was taken as reference molecular.Results Twenty of(S)-1-(2-(disubstituted methylamino)acetyl)pyrrolidine-2-carb-onitrile derivatives were synthesized, and which were confirmed by 1H NMR and MS. The molecular docking results showed that all title compounds show well binding affinity with target enzyme DPP-4. The docking score of most compounds are higher than reference molecular LAF-237. The patterns of the target compounds binding with DPP-4 interactions demonstrate that the cyanopyrrolidine moiety and the methylamino moiety were located on the P1 and P2 pockets respectively. Also, hydrogen bonds were observed between DPP-4 with some moieties, like cyano, carbonyl oxygen and proton amine. The result of drug-likeness evaluation of target compounds showed all the target compounds complied with the Lipinski rule, the values of TPSA, MV and RB forecasted the good permeability of these compounds, which explained their good pharmacokinetic properties.Conclusion(S)-1-(2-(disubstituted-methylamino)acetyl)pyrrolidine-2-carbonitrile derivatives were synthesized and confirmed by 1H NMR and MS, and their interactions with targer protein investigated by molecular docking study. The derivatives show good binding affinity with DPP-4 and possess potential DPP-4 inhibitory activity. As expected, all the target compounds complied with the drug-likeness properties, which indicating the title compounds have good further potencial for development.