Skin aging and wrinkle formation are processes that are largely influenced by the overexpression of enzymes like tyrosinase, elastase, and collagenase. This study aimed to validate the skin anti-aging properties of phytochemicals from Peperomia pellucida (PP) as well as its attendant mechanism of action. Compounds previously characterized from PP were retrieved from the PubChem database and docked to the active sites of tyrosinase, elastase, and collagenase using Schrödinger’s Maestro 11.5 and AutoDock tools to predict compounds with the best inhibitory potential to block these enzymes in preventing skin aging. It was observed that our hit compounds had favorable affinity and displayed key interactions at the active sites of these enzymes similar to those of the standards. With elastase, we observed key interactions with the amino acids in the S1 sub-pocket (especially ALA-181), Zn chelation, and histidine residues, which are key for inhibitory activity and ligand stability. The hit compounds showed H-bonds with the key amino acids of collagenase, including LEU-185 and ALA-186; phlobaphene and patuloside B were found to have better docking scores and inhibition constants (Ki) (−12.36 Kcal/mol, 0.87 nM and −12.06 Kcal/mol, 1.45 nM, respectively) when compared with those of the synthetic reference compound (−12.00 Kcal/mol, 1.67 nM). For tyrosinase, our hit compounds had both better docking scores and Ki values than kojic acid, with patuloside B and procyanidin having the best values of −9.43 Kcal/mol, 121.40 nM and −9.32 Kcal/mol, 193.48 nM, respectively (kojic acid = −8.19 Kcal/mol, 898.03 nM). Based on this study, we propose that acacetin, procyanidin, phlobaphene, patulosides A and B, palmitic acid, and hexahydroxydiphenic acid are responsible for the anti-aging effects of PP on the skin, and that they work synergistically through a multi-target inhibition of these enzymes.
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