The Osteogenic Potential of Oligopeptides Derived from Black Bean: Insights into Structure–Activity Relationship

Food-derived oligopeptides have emerged as promising natural candidates for antiosteoporosis therapy due to their remarkable osteogenic activity. However, the structure-osteogenic activity relationship of these oligopeptides remains poorly defined. In this study, we investigated for the first time the correlation between the structural characteristics and osteogenic effects of black bean-derived oligopeptides. Among the 70 oligopeptides analyzed, 36, 29, and 30 oligopeptides were found to significantly enhance the proliferation (108.28%-136.78%), differentiation (115.02%-182.41%), and mineralization (110.91%-159.41%) of MC3T3-E1 cells, respectively. Notably, tetrapeptides demonstrated marked efficacy in inducing osteogenesis <i>in vitro</i>, with their mineralization activity significantly correlated with their isoelectric point (pI) values and net charge. Tetrapeptides containing lysine residues, such as KIGT and KGVG, were particularly effective in stimulating osteogenic mineralization. Furthermore, reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) models were successfully established for all of the tetrapeptides. Importantly, the potent osteogenic tetrapeptides were characterized by bulky, electropositive, or hydrogen-bond acceptor groups at the R1 side chain of the N-terminal, along with electronegative or non-hydrogen bond acceptor groups at the R3 position and electronegative or hydrogen-bond acceptor groups at the R4 side chain of the C-terminal. Additionally, network pharmacology analysis highlighted the potential application of these osteogenic tetrapeptides in osteoporosis interventions. In conclusion, our findings demonstrated that the osteogenic activity of black bean-derived oligopeptides is attributed to their specific amino acid composition and structural features, providing novel insights for the efficient discovery and optimization of food-derived osteogenic oligopeptides.