AUTHOR=Cano Leydy , Soto-Ospina Alejandro , Araque Pedronel , Caro-Gomez Maria Antonieta , Parra-Marin Maria Victoria , Bedoya Gabriel , Duque Constanza TITLE=Diffusion Mechanism Modeling of Metformin in Human Organic Cationic Amino Acid Transporter one and Functional Impact of S189L, R206C, and G401S Mutation JOURNAL=Frontiers in Pharmacology VOLUME=11 YEAR=2021 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.587590 DOI=10.3389/fphar.2020.587590 ISSN=1663-9812 ABSTRACT=

Metformin used as a first-line drug to treat Type 2 Diabetes Mellitus is transported via organic cation channels to soft tissues. Mutations in the SLC22A1 gene, such as Gly401Ser, Ser189Leu, and Arg206Cys, may affect the drug’s therapeutic effect on these patients. This study aims at proposing a potential structural model for drug interactions with the hOCT1 transporter, as well as the impact of these mutations at both topological and electronic structure levels on the channel’s surface, from a chemical point of view with, in addition to exploring the frequency distribution. To chemically understand metformin diffusion, we used an open model from the protein model database, with ID PM0080367, viewed through UCSF Chimera. The effect of the mutations was assessed using computational hybrid Quantum Mechanics/Molecular Mechanics, based on the Austin Model 1 semi-empirical method using Spartan 18’ software. The results demonstrate coupling energy for metformin with amino acids F, W, H and Y, because of the interaction between the metformin dication and the electron cloud of π orbitals. The mutations analyzed showed changes in the chemical polarity and topology of the structure. The proposed diffusion model is a possible approach to the interaction mechanism between metformin and its transporter, as well as the impacts of variants, suggesting structural changes in the action of the drug. Metformin efficacy considerably varies from one patient to another; this may be largely attributed to the presence of mutations on the SLC22A1 gene. This study aims at proposing a potential structural model for metformin-hOCT1 (SLC22A1) transporter interaction, as well as the identification of the effect of mutations G401S (rs34130495), S189L (rs34104736), and R206C (616C > T) of the SLC22A1 gene at the topological and electronic structure levels on the channel surfaces, from a chemical viewpoint. Our results demonstrated that the coupling energies for metformin with aromatic amino acids F, W, H and Y, because of the interaction between the metformin dication and the electron cloud of π orbitals. Changes in the chemical environment’s polarity and the structure’s topology were reported in the mutations assessed. The diffusion model proposed is a potential approach for the mechanism of interaction of metformin with its transporter and the effects of variants on the efficacy of the drug in the treatment of type 2 diabetes. The assessment of the frequency of these mutations in a sample of Colombian type 2 diabetes patients suggests that different SLC22A1 gene variants might be involved in reduced OCT1 activity in the Colombian population since none of these mutations were detected.