Exploring non-covalent interactions for metformin-thyroid hormones stabilization: Structure, Hirshfeld atomic charges and solvent effect

Metformin has long been known as an inexpensive and active molecule for the type 2 diabetic treatments, yet its role as a thyroid nodule reagent is an active area of research. Here, the molecular interaction between metformin (MET) and different thyroid hormones (TSH) analogues such as T3, rT3, and T4 were investigated using DFT calculations (wB97XD/def2tzvpp). The non-covalent interactions stabilizes the TnMET adducts were investigated by exploring the molecular electrostatic potential. Hydrogen bonding (FIB) and Van der Waals (vdW) forces were responsible for the binding in TnMET adducts. The nature of the stabilizing forces was confirmed by the reduced density gradient (RDG) analysis and non-covalent interactions isosurface plots (NCI). Stabilization of the Tn and TnMET were investigated both in the gas phase and H2O. TnMET adducts stability increases was in the order T4MET>T3MET> rT3MET in the gas phase, while in aqueous phase rT3MET was the most stable adduct. The stability of rT3MET in H2O was in accordance with the increased both dipole moment and charge transfer from MET to rTn in H2O. The selectivity of MET binding with Tn in the gas phase and H2O helps the future understanding of nodule treatment clinical results. (C) 2020 Elsevier B.V. All rights reserved.