Metformin and glitazones: does similarity in biomolecular mechanism originate from tautomerism in these drugs?

Abstract

This theoretical study attempts to find out similarity between metformin and glitazone class of antidiabetic drugs. It was found that some tautomeric forms of both metformin and thiazolidinedione ring of glitazones have similar molecular electrostatic potential (MESP) surface and may bind to a common complementary surface. Complexation and docking studies were also carried out in order to support this hypothesis.

Tautomerism in drugs with benzimidazole carbamate moiety: an electronic structure analysis

“…Considering the importance of the tautomerism in drug molecules in the recent past [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41], the current results on the tautomerism of benzimidazole carbamates drugs may gain importance.…”

“…Our group reported the detailed electronic structure studies, conformational and tautomeric preferences on aminoguanidine, biguanide, guanylthiourea, sulfonylurea, and guanylurea derivatives, which are therapeutically important [33][34][35][36][37][38][39][40][41]. Lipkowitz and McCracken performed semi-empirical (MNDO) studies on albendazole, oxibendazole, etc., to understand the conformational tautomerism in these molecules [42][43][44][45].…”

Metformin, cancer and glucose metabolism

“…Thus, oral absorption, hepatic uptake and renal excretion of metformin are mediated by OTCs, reflecting the distribution, elimination and biochemical effects of metformin in tissues and subcellular compartments (Graham et al 2011). As other biguanides have been already demonstrated to encompass a unique set of pharmacophore features conferring the ability to adapt to different biological targets, pharmacological effects can be conceivably diverse and adaptable to different tautomeric forms (Sundriyal et al 2008). While this behaviour contributes to the puzzling polypharmacological role of metformin, several studies have recently contributed to uncovering mechanistic insights into key enzymes involved in the glycolytic pathway (Da Silva et al 2010.…”

“…1) offer a combination of unique chemical features allowing the possibility of easy ionization and tautomerization and thus constituting a privileged pharmacophore-interacting moiety with a drug-like scaffold suggestive of in vivo pharmacokinetics (Sundriyal et al 2008). Among biguanides, metformin can be considered as a particular case because it is a small and highly hydrophilic molecule, which is not bound to plasma proteins, is readily filtered at the glomerulus and is poorly resorbed due to its low lipid solubility, overall resulting in high renal clearance.…”

Tales from the war on error: the art and science of curating QSAR data

“…7) can be thought of as guanidines in which the electron withdrawing substituent is an amidine. Here, the lowest energy tautomer is one in which the central nitrogen bears no hydrogen, as reported by Sundriyal et al [42] The PubChem structure is much more realistic than that given in the WDI, differing only slightly from the lowest energy tautomer. The three metformin tautomers shown share a pair of common conjugate bases, so the identity of the dominant tautomer can be deduced from the respective basicities: at any given pH, the most basic tautomer will dominate.…”