Why Should Metformin Not Be Given in Advanced Kidney Disease? Potential Leads from Computer Simulations

Abstract

Metformin is considered as the go-to drug in the treatment of diabetes. However, it is either prescribed in lower doses or not prescribed at all to patients with kidney problems. To find a potential explanation for this practice, we employed atomistic-level computer simulations to simulate the transport of metformin through multidrug and toxin extrusion 1 (MATE1), a protein known to play a key role in the expulsion of metformin into urine. Herein, we examine the hydrogen bonding between MATE1 and one or more metformin molecules. The simulation results indicate that metformin continuously forms and breaks off hydrogen bonds with MATE1 residues. However, the mean hydrogen bond lifetimes increase for an order of magnitude when three metformin molecules are inserted instead of one. This new insight into the metformin transport process may provide the molecular foundation behind the clinical practice of not prescribing metformin to kidney disease patients.

Platinum–Acridine Agents with High Activity in Cancers Expressing the Solute Carrier MATE1 (SLC47A1)

“…This binding geometry may represent the first step in the recognition of MATE1 by PAs after entering the central cleft produced by the C- and N-lobes (see SI for additional views of the docked PAs). Functional analysis of hMATE1 mutants by site-directed mutagenesis in conjunction with transport assays have demonstrated that highly conserved Glu-273, Glu-278, Glu-300, and Glu-389 are critical for substrate translocation. , Homology models inspired by eukaryotic MATE1 strongly suggest that the C-lobe with its conserved acidic amino acid residues (Glu-273, Glu-389) and H-bonding network does not only mediate proton antiport but also harbors residues critical for transport efficiency and substrate selectivity. , Finally, recent docking and molecular dynamics simulations on the MATE1-mediated extrusion of the antidiabetic drug metformin show intermolecular interactions with Glu-273, Trp-274, Tyr-277, and Glu-389, which are also observed for the docked PAs. Thus, the ligand geometries observed for the PAs are consistent with the previously proposed mechanism of hMATE1-mediated substrate transport.…”