Abstract
Objective: The aim of the present study was to investigate the mode and mechanism of interactions involved towards binding of valganciclovir (VGC) with Human Serum Albumin (HSA) by spectroscopic and molecular modeling studies which can be extrapolated for the ten folds increase of bioavailability over its prodrug galanciclovir.Methods: Herein we employed fluorescence spectroscopy for evaluating the binding constant value, site of interaction and changes in the microenvironment of HSA fluorophores. Circular dichroism (CD) and UV-Visible spectroscopy is used for conformational changes of HSA in the event of binding of valaganciclovir. These experimental studies were further corroborated with molecular modeling studies.Results: Considerable quenching of fluorescence intensities of fluorophores in the presence of VGC showed that VGC interacts with HSA strongly with a binding constant of 4.11x104 M-1 with a free energy change of-6.26 Kcal/mol. Synchronous fluorescence and CD studies show that the microenvironment and confirmation of HSA are slightly altered in the presence of VGC. Though site marker experiments does not give any clue for identification of site, molecular docking studies showed that VGC binds to site IB of HSA.Conclusion: The weaker dominant electrostatic interactions with minor contributions of hydrophobic interactions of VGC with HSA at site IB (catalytic domain) might be the probable reason for the relative increase of hydrolysis of VGC to galanciclovir. And moderate binding constant value with HSA implies that HSA can be able to transport VGC under physiological conditions.
Highlights
Diseases that are prevailing and emerging due to infections are rapidly increasing in the present day due to the confluence of socio-economic factors
It is believed that the mode of infection of CMV follows the modes through which the human immune deficiency virus (HIV) is transmitted
Human serum albumin (HSA) provides a terminus in such a way that the drugs will be available beyond their soluble quantities in the plasma
Summary
All the working solutions are 1μM of HSA and VGC are titrated from 1 to 10μM for all the experiments performed unless mentioned. Such observations indicate that interactions exist between VGC and HSA and compliments with those of the results that are obtained from UV-Visible studies and conformational analysis This gradual decrease of fluorescence intensity or quenching suggests that VGC is interacting with HSA at the site, which is at the vicinity of trp-214. 7A it is evident that the fluorescence intensity of HSA-Pbz complex gradually decreased by the addition of VGC without considerable blue/red shifts and the binding constant for VGC in the presence of Pbz is found to be 1.20 x 104 M-1 Such a decrease in the binding constant value implies that the VGC might be approaching near to the Pbz binding site i. These results indicate that VGC is stabilized by dominant electrostatic interactions with little contributions of both hydrophobic and hydrophilic interactions which complement the results that are obtained from thermodynamic studies
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