Biomolecular Mode of Action of Metformin in Relation to Its Copper Binding Properties

Abstract

Metformin (Metf), the most commonly used type 2 diabetes drug, is known to affect the cellular housekeeping of copper. Recently, we discovered that the structurally closely related propanediimidamide (PDI) shows a cellular behavior different from that of Metf. Here we investigate the binding of these compounds to copper, to compare their binding strength. Furthermore, we take a closer look at the electronic properties of these compounds and their copper complexes such as molecular orbital interactions and electrostatic potential surfaces. Our results clearly show that the copper binding energies cannot alone be the cause of the biochemical differentiation between Metf and PDI. We conclude that other factors such as pKa values and hydrophilicity of the compounds play a crucial role in their cellular activity. Metf in contrast to PDI can occur as an anion in aqueous medium at moderate pH, forming much stronger complexes particularly with Cu(II) ions, suggesting that biguanides but not PDI may induce easy oxidation of Cu(I) ions extracted from proteins. The higher hydrophobicity and the lack of planarity of PDI may further differentiate it from biguanides in terms of their molecular recognition characteristics. These different properties could hold the key to metformin's mitochondrial activity because they suggest that the drug could act at least in part as a pro-oxidant of accessible protein-bound Cu(I) ions.

A computational study about the mechanism of action of metformin on hepatic gluconeogenesis, focused on its ability to create stable pseudo-aromatic copper complexes

“…So in both cases I. and II. above, the suggested mechanisms are able to fit with both with the experimental data of (Madiraju et al, 2014) and with the ideas that mitochondrial high pH (Repiščák et al, 2014), copper (Logie et al, 2012Annapurna & Rao, 2007) and pseudo-aromaticity in metformin complexes (Repiščák et al, 2014), must be involved.…”

“…Supplementary insight on the issue is given by four other studies that target the interaction of biguanides with copper and the metal role in their action. (Repiščák et al, 2014) shows that, among biguanides, metformin is not only the best at inhibiting gluconeogenesis, but it's the most effective at forming stable pseudo-aromatic copper complexes, suggesting a correlation between the two facts. Moreover, the complex stability increases with deprotonation, an event that is more likely to happen in the high pH environment of mitochondria.…”

“…The dimetformin (Figure 2.2) square planar copper complex was created in Discovery Studio (Dassault Systèmes, 2016) using the bond distances reported in (Repiščák et al, 2014).…”

“…The planar pseudo-aromatic structures of the complexes were realised using the (Repiščák et al, 2014) hypothesis of a metal coordination through a s-donation and a p-backdonation with a delocalised p ring system being formed (Figure 3.24).…”

Metformin directly acts on mitochondria to alter cellular bioenergetics

“…One popular view is that metformin acts as an inhibitor of complex I of the electron transport chain. However, the notion that metformin acts directly on mitochondria to inhibit complex I is controversial [9-15]. Recent work on the sensitivity of cancer cells to the direct actions of metformin further highlighted the controversy surrounding the mode of action of metformin.…”