Spectroscopic and molecular docking studies reveal binding characteristics of nazartinib (EGF816) to human serum albumin

Abstract

The interactions of novel anti-cancer therapeutic agents with the different plasma and tissue components, specifically serum albumins, have lately gained considerable attention due to the significant influence of such interactions on the pharmacokinetics and/or -dynamics of this important class of therapeutics. Nazartinib (EGF 816; NAZ) is a new anti-cancer candidate proposed as a third-generation epidermal growth factor receptor tyrosine kinase inhibitor that is being developed and clinically tested for the management of non-small cell lung cancer. The current study aimed to characterize the interaction between NAZ and human serum albumin (HSA) using experimental and theoretical approaches. Experimental results of fluorescence quenching of HSA induced by NAZ revealed the development of a statically formed complex between NAZ and HSA. Interpretation of the observed fluorescence data using Stern–Volmer, Lineweaver–Burk and double-log formulae resulted in binding constants for HSA-NAZ complex in the range of (2.34–2.81) × 10 4 M –1 over the studied temperatures. These computed values were further used to elucidate thermodynamic attributes of the interaction, which showed that NAZ spontaneously binds to HSA with a postulated electrostatic force-driven interaction. This was further verified by theoretical examination of the NAZ docking on the HSA surface that revealed an HSA-NAZ complex where NAZ is bound to HSA Sudlow site I driven by hydrogen bonding in addition to electrostatic forces in the form of pi-H bond. The HSA binding pocket for NAZ was shown to encompass ARG 257, ARG 222, LYS 199 and GLU 292 with a total binding energy of −25.59 kJ mol –1 .

Unusually High Affinity of the PLK Inhibitors RO3280 and GSK461364 to HSA and Its Possible Pharmacokinetic Implications

“… a Thermodynamic parameters of the protein–drug binding. b Ref . c Ref . d Ref . e Ref . f Ref . g Ref . h Ref . i Ref . j Ref . k Ref . l Ref …”

Binding Studies of AICAR and Human Serum Albumin by Spectroscopic, Theoretical, and Computational Methodologies

“…UV-VIS absorption spectroscopy is a basic spectrometric method used to investigate structural changes that accompany the formation of bound ligand–protein complexes [ 27 , 28 ]. The aromatic amino acids in proteins, tryptophan and tyrosine, strongly contribute to UV absorption of proteins at 280 nm and 274 nm respectively.…”

Protein binding of 4-hydroxybenzoic acid and 4-hydroxy-3-methoxybenzoic acid to human serum albumin and their anti-proliferation on doxorubicin-sensitive and doxorubicin-resistant leukemia cells

“…It could be suggested that the spontaneous interaction between HSA and 4-HBA or VA had occurred in the systems. The negative value of ΔH and ΔS represented the hydrogen bonding and Van der Waals forces [ 28 , 29 ]. The results in Table 3 showed that the ΔH and ΔS values also were negative values in HSA-4-HBA and HSA-VA system, indicating that hydrogen bonds and Van der Waals forces contributed in the binding of HSA to 4-HBA or VA.…”