In-silico screening of bioactive phytopeptides for novel anti-ageing therapeutics

A metabolic network of energy-sensing molecular pathways drives the biological ageing process. Regulating certain network elements can help decelerate the ageing process and ameliorate ageing associated disorders. Bioactive phytopeptides are a prospective avenue for anti-ageing therapeutics and rejuvenation biotechnology. The present study investigates the potential of therapeutic plant peptides against cellular senescence by targeting three key proteins in the ageing network - target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). This investigation screened a library of reported bioactive peptides using standard cheminformatic methods including in-silico ADMET, molecular docking, molecular dynamics simulation and molecular mechanics calculation. The retrieved simulation data predict 25 diverse phytopeptides as potential safe and drug-like anti-ageing biologics with half-lives >20 h and bioavailability scores >0.40. The best docked peptide, Cycloleonuripeptide B, exhibited strong binding affinity and stable complex formation with mTOR (-17.5 kCal/mol), SIRT1 (-28.54 kCal/mol) and two active sites in AMPK (-41.8 kCal/mol; -36.0 kCal/mol) during molecular dynamics simulations. The computational study acts as a foundation for future laboratory and clinical research into the potential of repurposing therapeutic phytopeptides against cellular senescence and associated pathophysiology. Communicated by Ramaswamy H. Sarma.