Computational Evaluation of AMPK‐Activating Phytochemical Analogues Targeting Metabolic Memory in Type 2 Diabetes

ABSTRACT Metabolic Memory (MM) is a major contributor to the long‐term complications of type 2 Diabetes Mellitus (T2DM). This study aimed to identify natural activators of AMP‐activated protein kinase (AMPK), a central energy regulator with multiple downstream signaling roles implicated in MM by targeting its two allosteric sites to counteract MM‐associated diabetic complications. An integrative in silico and network‐pharmacology approach was employed. Several well‐established AMPK‐activating phytochemicals and approximately 50 structural analogs screened with two allosteric sites (sites 1; α‐β subunit and site 2; γ subunit) of AMPK, via molecular docking. Docking results identified four top‐scoring phytochemicals among 46 compound, coptisine (‐9.2 kcal/mol) and glabrene (‐10.3 kcal/mol) targeting the α‐β site, alongside luteolin (‐9.3 kcal/mol) and dihydromyricetin (‐10 kcal/mol) targeting γ site. The top‐scoring complexes were subjected to 100 ns molecular dynamics (MD) simulations which confirmed the overall stability of all four phytochemicals along with their respective standards. ADMET profiling shows pharmacokinetic properties expect dihydromyricetin, violated Lipinski's rule of 5, and Network pharmacology (probability confidence score more than 60%) mapped relevant disease pathways involvement of AGE‐RAGE and AMPK signaling pathways in mediating the therapeutic potential of these compounds. These findings provide a strong foundation for future experimental validation and the therapeutic development of MM‐targeted interventions.