Unique Features of Metformin: A Combined Experimental, Theoretical, and Simulation Study of Its Structure, Dynamics, and Interaction Energetics with DNA Grooves

Mondal, Sayantan and Samajdar, Rudra N and Mukherjee, Saumyak and Bhattacharyya, Aninda J and Bagchi, Biman (2018) Unique Features of Metformin: A Combined Experimental, Theoretical, and Simulation Study of Its Structure, Dynamics, and Interaction Energetics with DNA Grooves. In: JOURNAL OF PHYSICAL CHEMISTRY B, 122 (8). pp. 2227-2242.

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Abstract

There are certain small molecules that exhibit extraordinarily diverse biological activities. Metformin is one of them. It is widely used as an antidiabetic drug for type-two diabetes. Recent lines of evidence of its role in antitumor activities and increasing the survival rates of cancer patients (namely, colorectal, breast, pancreas, and prostate cancer) are emerging. However, theoretical studies of the structure and dynamics of metformin have not yet been fully explored. In this work, we investigate the characteristic structural and dynamical features of three monoprotonated forms of metformin hydrochloride with the help of experiments, quantum chemical calculations, and atomistic molecular dynamics simulations. We validate our force field by comparing simulation results to those of the experimental findings. Energetics of proton transfer between two planar monoprotonated forms reveals a low energy barrier, which leads us to speculate a possible coexistence of them. Nevertheless, among the protonation states, we find that the nonplanar tautomeric form is the most stable. Our calculated values of the self diffusion coefficient agree quantitatively with NMR results. Metformin forms strong hydrogen bonds with surrounding water molecules, and its solvation dynamics shows unique features. Because of an extended positive charge distribution, metformin possesses features of being a permanent cationic partner toward several targets. We study its interaction and binding ability with DNA using UV spectroscopy, circular dichroism, fluorimetry, and metadynamics simulation. We find a nonintercalative mode of interaction. Metformin feasibly forms a minor/major groove-bound state within a few tens of nanoseconds, preferably with AT rich domains. A significant decrease in the free energy of binding is observed when it binds to a minor groove of DNA.

Item Type:	Journal Article
Publication:	JOURNAL OF PHYSICAL CHEMISTRY B
Publisher:	AMER CHEMICAL SOC, 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
Additional Information:	Copy right for the article belong to AMER CHEMICAL SOC, 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
Department/Centre:	Division of Chemical Sciences > Solid State & Structural Chemistry Unit
Date Deposited:	27 Mar 2018 18:28
Last Modified:	27 Mar 2018 18:28
URI:	http://eprints.iisc.ac.in/id/eprint/59387

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