Peptide inhibition of the mTORC1 signaling: A trend in Cancer Therapeutics

Cancer is the second most leading cause of deaths in the world and has been manifested by various hallmarks including uncontrolled cell proliferation, increased cell survival, abnormal angiogenesis, eluding of antitumor immunity and acquisition of metabolic processes unique to cancers. Interestingly, mTOR signaling is found to be associated with all of these hallmarks which makes it the most appropriate choice for target therapies against cancer. Inhibition of the target protein by peptides designed by using the interfacial amino acids of its interacting partner is one of the approaches of target therapies. The same approach has been engaged here to inhibit association of the mTOR kinase and RHEB. The sequential amino acids of the mTOR kinase were utilized to design three different native peptides which were further modified by incorporating evolutionary changes as the mutations. All the peptides were tested for their affinity with the RHEB by performing protein-peptide docking on the HADDOCK 2.4 docking interface and the binding energy calculation on the FoldX5.0 interface. Also, the interactions were analyzed using the ligplot + tool. The peptide H2P1 and H3P1 showed good binding energies (-14.28 kcal/mol and − 14.53 kcal/mol, respectively) in comparison to the entire mTOR-RHEB complex (-15.83 kcal/mol). This was also supported by a good number of Hydrogens bonds and other positive interactions. All these evidences support their potency to interrupt the mTORC1 signaling which can be further established based on these shreds of evidences.