Transition Metal–Metformin Complexes Modulate the Physicochemical Properties of Biguanides and Exhibit Stable Binding at the AMPK ADaM Site

Coordinating metformin to transition metals is a strategy to modulate the pharmacokinetic and pharmacodynamic profile of biguanide antidiabetics while preserving their favorable safety record. Here, we evaluated four previously synthesized and structurally characterized metformin complexes: [Co(Met)2(Met−)]Cl2·2H2O, [Ni(Met)(Met−)]Cl·H2O, [Cu(Met)2]Cl2·H2O and [Zn(MetH+)Cl3] (Co-met, Ni-met, Cu-met and Zn-met), as candidate allosteric modulators of the allosteric drug and metabolite site (ADaM) of AMP-activated protein kinase (AMPK; PDB 6C9F), benchmarked against metformin, phenformin and buformin. DFT-derived solvation free energies (ωB97X-D/def2-TZVP//def2-SVP, SMD), evaluated for the cationic complexes as their neutral chloride ion pairs, placed them above the free biguanides in lipophilicity (log P 5.17, 3.61 and 2.93 for the cobalt, nickel and copper compounds against 0.71–1.58 for the biguanides), whereas the neutral zinc complex showed no preference between phases. Docking at the ADaM site, validated by redocking the co-crystallized activator R734 to 0.50 Å RMSD (−11.21 kcal mol−1), ranked phenformin highest among the test compounds (−7.87 kcal mol−1), followed by Ni-met (−7.10), Cu-met (−7.09) and Co-met (−6.61). Across three independent 200 ns replicas per system (600 ns of aggregated sampling), the Co-, Ni- and Cu-met complexes remained bound to the ADaM pocket in every frame (ligand RMSD 4.2, 5.0 and 6.3 Å) and Zn-met for 88% of the sampling, as did the reference activator R734, which showed the narrowest range of the series (3.3 ± 1.3 Å). These results identified the metformin–transition metal complexes, particularly Co-met, Ni-met and Cu-met, as stable AMPK ADaM-site binders and promising candidates for experimental evaluation as antidiabetic agents.