Abstract
Linifanib (LNF) possess antitumor activity and acts by inhibiting receptor tyrosine kinase VEGF and PDGF. The interaction of BSA with the drug can provide valuable information regarding the pharmacokinetic and pharmacodynamics behavior of drug. In our study the spectrophotometric methods and molecular docking studies were executed to understand the interaction behavior of BSA and LNF. BSA has an intrinsic fluorescence and that fluorescence was quenched by LNF. This quenching process was studied at three different temperatures of 288, 300and 308 K. The interaction between LNF and BSA was due to static quenching because the Ksv (Stern-Volmer constant) at 288 K was higher than at 300 and 308 K. Kq (quenching rate constant) behaved in a similar fashion as the Ksv. Several other parameters like binding constants, number of binding sites and binding energy in addition to molecular docking studies were also used to evaluate the interaction process. A decrease in the binding constants was observed with increasing temperatures and the binding site number approximated unity. The decreasing binding constant indicates LNF–BSA complex stability. The site mark competition experiment confirmed the binding site for LNF was located on site II of BSA. UV–visible studies along with synchronous fluorescence confirm a small change in the conformation of BSA upon interaction with LNF. The thermodynamic analysis provided the values for free energy ΔG0, ΔH0 and ΔS0. The ΔG0 at the 288, 300 and 308 K ranged in between -21.5 to -23.3 kJ mol-1, whereas the calculated values of ΔH (-55.91 kJ mol-1) and ΔS0 (-111.74 J mol-1·K-1). The experimental and molecular docking results suggest that the interaction between LNF and BSA was spontaneous and they exhibited hydrogen bonding and van der Waals force between them.
Highlights
Once the drug molecule reaches the systemic circulation it interacts with several biomolecules and this interaction with proteins play a vital role in the pharmacokinetics of drugs [1,2]
The serum albumin interacts with drugs in systemic circulation, studying these binding interactions provides a greater insight into the drug therapy
In addition to albumin the drug ligands bind to other proteins such as human holo-transferrin
Summary
Once the drug molecule reaches the systemic circulation it interacts with several biomolecules (predominantly proteins) and this interaction with proteins play a vital role in the pharmacokinetics (absorption, distribution, metabolism and excretion) of drugs [1,2]. Studying such interactions is important during the drug discovery and development [3,4,5,6,7,8,9,10,11]. The level at which the drug bind to the protein determines its distribution volume and rate of elimination form the body These interaction studies provide a valuable evidence about the structural features and therapeutic efficacy of the drug [29,30,31]. This study is anticipated to give a significant insight to further elucidate the in-vivo storage and transport mechanism of LNF and its pharmacokinetics
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