title: Investigation on the protein-binding properties of icotinib by spectroscopic and molecular modeling method.
abstract: Icotinib is a highly-selective epidermal growth factor receptor tyrosine kinase inhibitor with preclinical and clinical activity in non-small cell lung cancer, which has been developed as a new targeted anti-tumor drug in China. In this work, the interaction of icotinib and human serum albumin (HSA) were studied by three-dimensional fluorescence spectra, ultraviolet spectra, circular dichroism (CD) spectra, molecular probe and molecular modeling methods. The results showed that icotinib binds to Sudlow's site I in subdomain IIA of HSA molecule, resulting in icotinib-HSA complexes formed at ground state. The number of binding sites, equilibrium constants, and thermodynamic parameters of the reaction were calculated at different temperatures. The negative enthalpy change (ΔH(θ)) and entropy change (ΔS(θ)) indicated that the structure of new complexes was stabilized by hydrogen bonds and van der Waals power. The distance between donor and acceptor was calculated according to Förster's non-radiation resonance energy transfer theory. The structural changes of HSA caused by icotinib binding were detected by synchronous spectra and circular dichroism (CD) spectra. Molecular modeling method was employed to unfold full details of the interaction at molecular level, most of which could be supported by experimental results. The study analyzed the probability that serum albumins act as carriers for this new anticarcinogen and provided fundamental information on the process of delivering icotinib to its target tissues, which might be helpful in understanding the mechanism of icotinib in cancer therapy.
authors.affiliation: College of Chemical and Pharmaceutical Engineering, Jingchu University of Technology, Jingmen, Hubei 448000, People's Republic of China.
authors.forename: Hua-xin
authors.initials: HX
authors.lastname: Zhang
authors.affiliation: College of Chemical and Pharmaceutical Engineering, Jingchu University of Technology, Jingmen, Hubei 448000, People's Republic of China.
authors.forename: Hang-xing
authors.initials: HX
authors.lastname: Xiong
authors.affiliation: College of Chemical and Pharmaceutical Engineering, Jingchu University of Technology, Jingmen, Hubei 448000, People's Republic of China. Electronic address: jmlilwei1005@163.com.
authors.forename: Li-wei
authors.initials: LW
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism*; D001665:Binding Sites; D002942:Circular Dichroism; D043844:Crown Ethers / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000378:metabolism*; D011799:Quinazolines / Q000378:metabolism*; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D043844:Crown Ethers; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012709:Serum Albumin; C531470:icotinib; D066246:ErbB Receptors
keywords: Binding site; Energy transfer; Human serum albumin; Icotinib; Molecular modeling