Insight into the binding behavior of ceritinib on human α-1 acid glycoprotein: Multi-spectroscopic and molecular modeling approaches.

Abstract

Ceritinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor for mainly treating non-small cell lung cancer (NSCLC). This investigation focused on to clarify in detail the binding behavior between human α-1 acid glycoprotein (HAG) and ceritinib by means of multi-spectroscopic and molecular modeling approaches. Fluorescence data obtained at four different temperatures indicated ceritinib quenched the endogenous fluorescence of HAG by a static quenching mechanism. Based on the Kb value at 105M-1 level, it can be inferred that the binding affinity between both is strong. From findings of thermodynamic parameter analysis, the competitive experiments with ANS and sucrose as well as molecular dynamic (MD) simulation, it can be inferred that hydrophobicity, hydrogen bonding, van der Waals forces as well as electrostatic interactions exist in the binding interaction between ceritinib and HAG. The findings from UV absorption, circular dichroism, and synchronous fluorescence spectroscopy indicated that the change in the microenvironment around the protein structure, secondary structure and tryptophan residues occurred after interaction with ceritinib. The data from FRET analysis confirmed that the non-radiative energy transfer between the two existed and the binding distance between the acceptor (ceritinib) and donor (HAG) was 2.11nm. Meantime, the influence of Ca2+, Cu2+, Ni2+, Co2+, and Zn2+ ions on the binding interaction of ceritinib with HAG were obvious, especially Zn2+ ion.