Discovering protein-binding peptides via in silico screening: From methodology to application

Peptides are short amino acid chains that often change conformation upon protein binding. Protein–peptide interactions play vital roles in many cellular processes, and therapeutic peptides are gaining significant attention for their predictable metabolism, high selectivity, and reduced off-target effects compared with small molecules. However, a major bottleneck remains: the lack of a large-scale in silico screening method for specific protein targets. While such methods have accelerated small-molecule discovery, peptide flexibility and sequence diversity make similar approaches challenging. Here, we developed MDockPeP2_VS, a computational method that integrates molecular docking with structural conservation between protein folding and protein–peptide binding. We found that when interfacial residues are conserved, a sequence fragment from a monomeric protein tends to bind a target protein with a similar conformation. This insight dramatically reduces conformational search space and computational cost, making in silico peptide screening practical. We applied MDockPeP2_VS to design peptide inhibitors targeting TEM-1 β-lactamase of Escherichia coli, a key enzyme in antibiotic resistance.