A Computational Study About The Mechanism Of Action Of Metformin On Hepatic Gluconeogenesis, Focused On Its Ability To Create Stable Pseudo-Aromatic Copper Complexes

Metformin is the best therapeutic choice for treating type 2 Diabetes.\n\nDespite this, and the fact it has been prescribed worldwide for decades, its mechanism of gluconeogenesis inhibition is still unknown.\n\nIn the following work a novel mechanism of inhibition is suggested: that metformin performs its action on the target enzyme not as a pure molecule but, after sequestering endogenous cellular copper, as a copper complex.\n\nThis result was obtained using chemoinformatics methods including homology modeling for the creation of the target enzymes tridimensional virtual structure, molecular docking for both the determination of the movement of the prosthetic group inside its cavity and for the identification of the best ligand poses for the metformin copper complexes, and eventually pharmacophore modeling and virtual screening to find alternative virtual leads that could achieve similar effects.\n\nThe simulations show the complex binding as a non competitive inhibitor to the large exit of the mitochondrial glycerophosphate dehydrogenase enzymes FAD cavity, preventing FAD movement inside the cavity and/or quinone interaction and therefore its electron transfer function.\n\nThe proposed mechanism seems to be successful at explaining a wide range of existing experimental results, both regarding measurements of metformin non-competitive inhibition of GPD2 and the role of copper and pH in its action.\n\nThe virtual screening outcome of at least two similarly active purchasable molecule hints to an easy way to experimentally test the proposed mechanisms.\n\nIn fact, the virtual leads are very similar to the copper complex but quite different from metformin alone, and a laboratory confirmation of their activity should plausibly imply that metformin acts in synergy with copper, giving us the ability to design new antidiabetic drugs in a novel and more rational fashion, with significant savings in research costs and efforts.