In Silico Docking Study of Berberine Derivatives as AMPK Activators for Diabetes Mellitus via Multi-Target Protein Approach.

ABSTRACT: The present in-silico study explored the molecular interaction and pharmacokinetic behavior of Berberine (BBR) derivatives as potential activators of AMP-activated protein kinase (AMPK), a crucial metabolic regulator involved in Type 2 Diabetes Mellitus. The three-dimensional crystal structure of AMPK was obtained from the Protein Data Bank (https://www.rcsb.org), and eleven Berberine derivatives (Molecules 1–11) were designed and optimized using Chem-Sketch. Their three-dimensional structures were saved in SDF format and docked with AMPK using the CB-Dock web server (http://clab.labshare.cn/cb-dock/). Docking simulations predicted optimal binding orientations and estimated binding affinities, while visual analyses identified key hydrogen bonds, hydrophobic contacts, and electrostatic interactions stabilizing the complexes. ADME profiling demonstrated high gastrointestinal (GI) absorption for all compounds, suggesting favorable oral bioavailability and efficient membrane permeability. Molecules 1–7 were predicted to cross the blood–brain barrier (BBB), indicating potential central metabolic effects, whereas Molecules 8–11 were restricted to peripheral tissues, minimizing CNS-related side effects. Most compounds acted as P-glycoprotein (Pgp) substrates, implying active efflux and detoxification potential. Cytochrome P450 (CYP) enzyme inhibition analysis showed that Molecules 1, 3, 4, 5, 6, and 7 had broad inhibitory potential toward major metabolic isoforms, while Molecules 2 and 8–11 displayed selective inhibition, suggesting lower risks of drug–drug interactions. Low skin permeability values (log Kp = −4.99 to −5.86 cm/s) confirmed their suitability for oral delivery. According to Lipinski’s Rule of Five, Molecules 1, 2, 3, 5, 6, and 7 fulfilled all drug-likeness criteria, exhibiting optimal physicochemical properties. Overall, the combined molecular docking and pharmacokinetic analyses identified multiple Berberine derivatives with strong AMPK binding affinity and favorable pharmacokinetic profiles. These compounds represent promising leads for AMPK-targeted antidiabetic drug development with the molecular dynamics validation, though further in-vitro and in-vivo validation is required to confirm their therapeutic potential.