Mechanistic physicochemical insights into glycation and drug binding by serum albumin: Implications in diabetic conditions

Abstract

The drug binding ability of serum albumin might get affected as a result of its glycation under diabetic conditions. It requires not only an understanding of the effect of glycation of the protein upon association with the drug, but also calls for an assessment of structure-property-energetics relationships. A combination of ultrasensitive calorimetric, spectroscopic and chromatographic approach has been employed to correlate thermodynamic signatures with recognition, conformation and mechanistic details of the processes involved. An important observation from this work is that 3-(dansylamino) phenyl boronic acid (DnsPBA) assay cannot always determine the extent of glycation as evidenced by MALDI-TOF mass spectra of glycated HSA due to its selectivity for 1,2 or 1,3 cis-diol structures which may be absent in certain AGEs. Protein gets modified post glycation with the formation of advanced glycation end products (AGEs), which are monitored to be targeted by the guanidine group present in anti-diabetic drugs. AGEs formed in the third and fourth week of glycation are significant in the recognition of anti-diabetic drugs. The results with metformin and aminoguanidine suggest that the extent of binding depends upon the number of guanidine group(s) in the drug molecule. Open chain molecules having guanidine group(s) exhibit stronger affinity towards glycated HSA than closed ring entities like naphthalene or pyridine moiety. The observation that the drug binding ability of HSA is not adversely affected, rather strengthened upon glycation, has implications in diabetic conditions. A rigorous structure-property-energetics correlation based on thermodynamic signatures and identification of functional groups on drugs for recognition by HSA are essential in deriving guidelines for rational drug design addressing diabetes.