Designing Therapeutic Peptides for Inhibiting the mTORC1 Signalling Pathway: A Novel Trend in Cancer Therapeutics

Cancer is the second leading cause of death globally, characterized by hallmark features including uncontrolled cell proliferation, enhanced survival, abnormal angiogenesis, immune evasion, and metabolic reprogramming. The mTOR signalling pathway intersects with all these hallmarks, positioning it as an attractive therapeutic target. One promising approach involves disrupting protein-protein interactions using peptides derived from interfacial amino acids of binding partners. This study employed such a strategy to inhibit the association between mTOR kinase and RHEB, a critical interaction for mTORC1 activation. Three native peptides were designed from the mTOR-RHEB interface sequence. These were further modified by incorporating evolutionarily conserved mutations observed in mTOR sequences. All peptides were evaluated for binding affinity with RHEB through protein-peptide docking using HADDOCK 2.4 and binding energy calculations via FoldX5.0. Interaction analyses were performed using LigPlot+. The peptides were designated N1-3 (native), M1-3 (mutated), and C1-3 (control). Among these, peptides M2 and M3 demonstrated binding energies of -14.28 kcal/mol and -14.53 kcal/mol, respectively, comparable to the complete mTOR-RHEB complex (-15.83 kcal/mol). These findings were supported by extensive hydrogen bonding and favourable intermolecular interactions. The results suggest that these peptides possess significant potential to disrupt mTORC1 signalling, warranting further validation through in vitro studies for cancer therapeutic applications.