Discovery of High-Affinity Glutamine-Derived Peptides from Wheat Gliadin Targeting CaSR: a Computational Approach Integrating Deep Learning and Molecular Dynamics

Calcium-sensing receptor (CaSR) -targeting agonist peptides play a crucial role in maintaining intestinal homeostasis. In this study, we integrated deep learning, virtual screening, and molecular simulation to develop PeptideMDI, an intelligent screening platform built on Nextflow. From 2798 candidate peptides derived from wheat gliadin, we identified RLSYQFPFYP (designated CaSRTP₁) as the lead peptide, which binds CaSR with a dissociation constant Kd = 74. 4 nM. Functionally, CaSRTP₁ upregulates tight junction proteins, promotes cell proliferation, enhances antioxidant defenses, and reduces the transcriptional levels of TNF-α, IL-8, and IL-6. Mechanistically, it attenuates H2O2 induced oxidative stress by activating the CaSR/PLCγ1/Rac1/MAPK signaling cascade. In conclusion, the CaSR-targeting peptide RLSYQFPFYP was identified with high affinity (nanomolar range) using PeptideMDI, establishing a scalable technological framework for discovering bioactive peptides that promote gut homeostasis and for designing next-generation smart peptide therapeutics.