Transition Metal–Metformin Complexes Modulate the Physicochemical Properties of Biguanides and Exhibit Stable Binding at the AMPK ADaM Site
6 affiliations
- 1Plataforma de Biología y Química Computacionales, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Panama City 0801, Panama
- 2Escuela de Ciencias Agrícolas, Pecuarias y del Medio Ambiente, Universidad Nacional Abierta y a Distancia (UNAD), Popayán 190001, Colombia
- 3Grupo de Investigación en Química y Biotecnología (QUIBIO), Facultad de Ciencias Básicas, Universidad Santiago de Cali, Cali 760035, Colombia
- 4Grupo de Investigación en Salud Integral (GISI), Facultad de Salud, Universidad Santiago de Cali, Cali 760035, Colombia
- 5Departamento de Química, Universidad Nacional de Colombia-Sede Bogotá, Bogotá 111321, Colombia
- 6Departamento de Química, Facultad de Ciencias Naturales, Exactas y de la Educación, Universidad del Cauca, Popayán 190001, Colombia
Abstract
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.
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BibTeX
@article{orjuela2026transition,
title = {{Transition Metal–Metformin Complexes Modulate the Physicochemical Properties of Biguanides and Exhibit Stable Binding at the AMPK ADaM Site}},
author = {Adrian L. Orjuela and Andrea Pastrana-Dávila and Yesid Armando Aristizabal-Salazar and Yamil Liscano-Martínez and Jorge Alí-Torres and Jose Oñate-Garzón and Richard F. D’Vries},
journal = {Inorganics},
year = {2026},
month = oct,
doi = {10.3390/inorganics14100259},
url = {https://www.mdpi.com/2304-6740/14/10/259},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Transition Metal–Metformin Complexes Modulate the Physicochemical Properties of Biguanides and Exhibit Stable Binding at the AMPK ADaM Site
AU - Adrian L. Orjuela
AU - Andrea Pastrana-Dávila
AU - Yesid Armando Aristizabal-Salazar
AU - Yamil Liscano-Martínez
AU - Jorge Alí-Torres
AU - Jose Oñate-Garzón
AU - Richard F. D’Vries
PY - 2026
DA - 2026/10/04
JO - Inorganics
DO - 10.3390/inorganics14100259
UR - https://www.mdpi.com/2304-6740/14/10/259
AB - 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.
SN - 2304-6740
ER -