article · 10/10/2015
Protonation-deprotonation and structural dynamics of antidiabetic drug metformin
Résumé
Since the late 1950s, metformin is the worldwide first-line pharmacologic treatment for type 2 diabetes. Beyond the fact that the mode of action of this drug has always been very difficult to elucidate, little is known about its physicochemical properties in aqueous solution. Herein, we focus on the protonation-deprotonation features of metformin by using jointly Raman scattering and theoretical calculations. Vibrational markers evidence the fact that within a wide pH interval extended at either side of the physiological one, i.e. similar to 7 +/- 4, metformin is mainly monoprotonated. Although the biprotonated form appears as major population at very low pH values (<1.5), Raman markers of neutral species do not dominate even at very high pH values (>13), presumably because of the extreme basicity of metformin as described by recent NMR measurements. Density functional theory calculations using both explicit and implicit hydration models, have led to presume a possible coexistence of two possible monoprotonated forms in aqueous environment. In conclusion, the biophysical features of this molecule and the amount used in clinical practice might certainly explain the pleiotropic actions toward several targets where metformin could be a permanent cationic partner, a proton donor/acceptor, as well as a good candidate for stabilizing the so-called pi ->pi interactions. (C) 2015 Elsevier B.V. All rights reserved.
Citer cet article
Hernandez, B., Pflueger, F., Kruglik, S.-G., Cohen, R., & Ghomi, M. (2015). Protonation-deprotonation and structural dynamics of antidiabetic drug metformin. Journal of Pharmaceutical and Biomedical Analysis, 114, 42-48. https://doi.org/10.1016/j.jpba.2015.04.041@article{Hernandez2015_22,
author = {Hernandez, Belen and Pflueger, Fernando and Kruglik, Sergei G. and Cohen, Regis and Ghomi, Mahmoud},
year = {2015},
month = {10},
title = {Protonation-deprotonation and structural dynamics of antidiabetic drug metformin},
journal = {Journal of Pharmaceutical and Biomedical Analysis},
publisher = {ELSEVIER SCIENCE BV},
volume = {114},
pages = {42-48},
address = {PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS},
abstract = {Since the late 1950s, metformin is the worldwide first-line pharmacologic treatment for type 2 diabetes. Beyond the fact that the mode of action of this drug has always been very difficult to elucidate, little is known about its physicochemical properties in aqueous solution. Herein, we focus on the protonation-deprotonation features of metformin by using jointly Raman scattering and theoretical calculations. Vibrational markers evidence the fact that within a wide pH interval extended at either side of the physiological one, i.e. similar to 7 +/- 4, metformin is mainly monoprotonated. Although the biprotonated form appears as major population at very low pH values (<1.5), Raman markers of neutral species do not dominate even at very high pH values (>13), presumably because of the extreme basicity of metformin as described by recent NMR measurements. Density functional theory calculations using both explicit and implicit hydration models, have led to presume a possible coexistence of two possible monoprotonated forms in aqueous environment. In conclusion, the biophysical features of this molecule and the amount used in clinical practice might certainly explain the pleiotropic actions toward several targets where metformin could be a permanent cationic partner, a proton donor/acceptor, as well as a good candidate for stabilizing the so-called pi ->pi interactions. (C) 2015 Elsevier B.V. All rights reserved.},
url = {http://www.dx.doi.org/10.1016/j.jpba.2015.04.041},
doi = {10.1016/j.jpba.2015.04.041},
issn = {0731-7085},
}TY - JOUR
AU - Hernandez, Belen
AU - Pflueger, Fernando
AU - Kruglik, Sergei G.
AU - Cohen, Regis
AU - Ghomi, Mahmoud
PY - 2015
DA - 2015/10/10
TI - Protonation-deprotonation and structural dynamics of antidiabetic drug metformin
JO - Journal of Pharmaceutical and Biomedical Analysis
VL - 114
PB - ELSEVIER SCIENCE BV
SN - 0731-7085
AB - Since the late 1950s, metformin is the worldwide first-line pharmacologic treatment for type 2 diabetes. Beyond the fact that the mode of action of this drug has always been very difficult to elucidate, little is known about its physicochemical properties in aqueous solution. Herein, we focus on the protonation-deprotonation features of metformin by using jointly Raman scattering and theoretical calculations. Vibrational markers evidence the fact that within a wide pH interval extended at either side of the physiological one, i.e. similar to 7 +/- 4, metformin is mainly monoprotonated. Although the biprotonated form appears as major population at very low pH values (<1.5), Raman markers of neutral species do not dominate even at very high pH values (>13), presumably because of the extreme basicity of metformin as described by recent NMR measurements. Density functional theory calculations using both explicit and implicit hydration models, have led to presume a possible coexistence of two possible monoprotonated forms in aqueous environment. In conclusion, the biophysical features of this molecule and the amount used in clinical practice might certainly explain the pleiotropic actions toward several targets where metformin could be a permanent cationic partner, a proton donor/acceptor, as well as a good candidate for stabilizing the so-called pi ->pi interactions. (C) 2015 Elsevier B.V. All rights reserved.
SP - 42
EP - 48
DO - 10.1016/j.jpba.2015.04.041
UR - http://www.dx.doi.org/10.1016/j.jpba.2015.04.041
ER -