Analysis of Structure–Activity Relationships of Food-Derived DPP IV-Inhibitory Di- and Tripeptides Using Interpretable Descriptors

This study aimed to analyze the structural requirements for di- and tripeptides exhibiting a DPP IV-inhibitory effect. The sequences of 46 di- and 33 tripeptides, including their bioactivity (IC50; μM), were implemented from the BIOPEP-UWM database, whereas modeling was performed using SCIGRESS Explorer: Version FJ 3.5.1 software. Models included 336 (dipeptide dataset) and 184 descriptors (tripeptide dataset). The values of the determination coefficient (R2) defining model reliability were 0.782 and 0.829 for di- and tripeptides, respectively. Based on the implemented descriptors, it was concluded that increased numbers of nitrogen atoms, as well as the methyl groups, are required for dipeptides to enhance the DPP IV-inhibitory effect. This was indicated by the presence of amino acids with an aliphatic side chain (e.g., Leu, Val, Ile) and an aromatic ring (Trp). In the case of tripeptides, a correlation was found between their molecular weight (MW) and studied bioactivity. A tripeptide with a molecular weight of up to 500 Da was found suitable for the sequence to act as the DPP IV inhibitor. Although there is still a gap in explaining the relations between the structural nature and the DPP IV-inhibitory activity of peptides, and certain issues related to this topic still remain unknown, the results are in line with those reported by other authors. Additionally, the suitability of the SCIGRESS tool in the QSAR analysis of peptides derived from foods can be confirmed. Interpretable descriptors enabled the achievement of more unequivocal results concerning the main structural factors affecting the DPP IV inhibition of di- and tripeptides.