Proteomic Identification and<em> In Silico</em> Polypharmacological Profiling of Alpha-2 Collagen Peptides from<em> Isostichopus badionotus</em> with Regenerative and Metabolic Potential

<jats:p>Marine invertebrates, particularly the sea cucumber (Isostichopus badionotus), represent a rich reservoir of bioactive collagen peptides with high biomedical potential. This study employed a combined proteomic and computational polypharmacology approach to identify and optimize low-molecular-weight (LMW) collagen peptides for regenerative and metabolic applications. LC-MS/MS analysis of a 1–3 kDa enzymatic hydrolysate derived exclusively from purified I. badionotus body wall collagen successfully identified Alpha-2 collagen as the primary constituent. Crucially, the analysis revealed the natural presence of both the angiogenic RGD (Arg-Gly-Asp) and osteogenic GPR (Gly-Pro-Arg) motifs. In silico blind molecular docking demonstrated that the native sequences possessed moderate polypharmacological affinities for Integrin α_V β_3, Dipeptidyl peptidase-4 (DPP4), and Cyclooxygenase-2 (COX-2). Rational structural modification yielded optimized variants (Loc1d and Loc2g) with vastly superior thermodynamic binding scores. Ultimately, a dual-motif chimeric peptide, Loc3a (YGPRGDPRG), was designed, achieving unparalleled binding against ACE (−225.12), DPP4 (−217.25), and Integrin αV β3 (−183.93). Physicochemical and ADMET profiling confirmed these peptides are exceptionally stable (Loc3a Instability Index = −36.17), non-allergenic, and possess a pharmacokinetic profile uniquely suited for safe, localized topical application. Supported by systems biology protein-protein interaction (PPI) networks, these findings position the rationally designed I. badionotus collagen derivatives as highly promising, multi-target therapeutic candidates for the simultaneous management of chronic wounds, oxidative stress, and metabolic dysregulation.</jats:p>