A Computational Strategy for Validation of Piperidine as Lead from Phytochemical evaluation for Antiglycation activity via AGEs-RAGE Pathway Modulation

Research Article

Abstract

This research work shows the potential of piperidine as a lead scaffold for inhibiting glycation, using a computational technique focused on the AGE-RAGE signaling pathway, a critical factor responsible for diabetic complications. Network pharmacology was applied to map overlapping gene targets between piperidine-containing phytochemicals and glycation processes. Protein-Protein Interaction (PPI) networks were subsequently constructed to identify hub genes, while biological relevance was interrogated through Gene Ontology (GO) and KEGG pathway enrichment analyses. To prove these findings, molecular docking simulations (Molegro Virtual Docker v.6.0) were carried out to determine the binding affinity of the compounds against the RAGE protein (PDB ID: 4LP5). The results indicated significant involvement in the AGE-RAGE, type II diabetes mellitus, and insulin resistance pathways, with MTOR, ESR1, HSP90AA1, NFKB1, and STAT3 emerging as central regulatory hubs. Docking results indicated that the phytochemicals possess strong binding affinity for the human RAGE protein, surpassing the affinity of the standard reference, Pyridoxamine. Specifically, consistent hydrogen bonding and steric interactions with key residues suggest a conserved, favorable binding mode within the active site. The results from this work conclude that polyhydroxy piperidine-based phytochemicals can be promising antiglycation agents that operate via multi-pathway modulation and direct RAGE inhibition, supporting the further development of piperidine-based synthetic pharmacophores