The Theoretical Substantiation of the Targeted Search for New DPP4 Inhibitors. Computational Studies of Potential Candidates

Abstract

Growing evidence suggests that dipeptidyl peptidase 4 (DPP4) inhibitors, in addition to their role in improving glycemic control, help to reduce endothelial dysfunction and have hypolipidemic, anti-atherosclerotic, antitumor, antiviral, and neurotropic properties. This multi-target property may be one of the reasons for repurposing therapeutic treatment strategies with existing agents and the basis for finding new agents to inhibit this target. Based on the structural prerequisites and the evolutionary path of creating DPP4 inhibitors, an inhibitory (R)-β-aminoamide base was used as the basis for constructing potential candidates. It contained a substituted piperazine-2-one derivative and (S)-pyrrolidine-2-carbonitrile fragment, as well as phenyl and diphenyl rings, which were additionally saturated with substituents of various electronic structures, in position 4 of the β-aminoamide chain. The construction of the molecules was carried out taking into account the correspondence of chiral centers to combinations of chiral chains at the DPP4 binding site to possibly prevent a decrease in the inhibitory activity. In silico assessment of the “drug-likeness” and pharmacokinetic profile of the group of compounds studied showed that it had favorable characteristics and could be recommended for further molecular docking in order to predict the likely inhibition of the catalytic activity of DPP4. According to the results of docking, molecules with a moderate and high affinity were found. A detailed analysis of the resulting complexes showed that only nine compounds had a binding mode similar to classical inhibitors. According to the calculated array of values and analysis of the results of docking among the derivatives tested, a hit compound was found as a promising DPP4 inhibitor.