Exploring the binding characteristics between lorlatinib and human alpha-1-acid glycoprotein: Multispectral and molecular modeling techniques

[Display omitted] •Lorlatinib (LOR) quenches the fluorescence of HAG by the mixed quenching and forms a LOR-HAG complex with moderate affinity.•Lorlatinib insets into the hydrophobic pocket in the central beta barrel of HAG.•Driving forces include hydrophobic forces, van der Waals forces and hydrogen bonds.•Binding of lorlatinib to HAG alters slightly the conformation of HAG.•The contribution of key residues to the binding between the two is analyzed. Approval in 2019 was granted for the highly selective, targeted agent lorlatinib, which primary target is ROS1 and ALK. The purpose of this work was to examine the binding mechanism between lorlatinib (LOR) and HAG employing multispectral and molecular modeling techniques. Fluorescence data demonstrated that LOR quenched HAG fluorescence as a static quenching, interecalated into the hydrophobic cavity of HAG with a moderate affinity. Thermodynamic and competitive experiments pointed out that LOR bound with HAG primarily through hydrogen bonding, hydrophobic, and van der Waals forces. Circular dichroism, three-dimensional and synchronous fluorescence spectroscopic studies noted that the secondary structure of HAG and microenvironments around tyrosine (Tyr) and tryptophan (Trp) residues were altered due to binding with LOR. The contribution of each energy involved in binding process of LOR and HAG has been analyzed by molecular simulation techniques. Besides, the environmental conditions with metal ions have also been studied. The present study is expected to provide a theoretical basis for further studying the metabolism of LOR in vivo, which may help to gain a deeper understanding of the general pharmacological activity of the drug.