Binding Behavior of Trelagliptin and Human Serum Albumin: Molecular Docking, Dynamical Simulation, and Multi-spectroscopy

This study aims to investigate the interaction mechanism of a hypoglycemic agent, trelagliptin (TLP), and human serum albumin (HSA) through computer simulation and assisted spectroscopy methods. Computer simulation including molecular docking and molecular dynamics analysis was conducted under physiological conditions. Molecular docking results indicate that TLP bound to HSA at site I, and the binding behavior was mainly governed by hydrophobic force. Competitive experiments further verified the theoretical conclusion from molecular docking. Molecular dynamics simulation revealed that TLP indeed stably bound to site I of HSA in the hydrophobic subdomain IIA. Moreover, TLP presented a certain effect on the structural compactness of HSA. In molecular dynamics simulation, hydrogen bonds appeared, which suggested the reliability and stability of the combination. The binding energy of the stable phase is around -250 kJ/mol. Fluorescence quenching studies and time-resolved fluorescence analysis indicated that the evident fluorescence quenching phenomenon of HSA could be due to TLP binding initiated by static quenching mechanism. The binding constants (K) of the complex were found to be around 10 via fluorescence data, and the calculated thermodynamic parameters indicated that hydrophobic force played major role in the binding of TLP to HSA. Synchronous fluorescence and three-dimensional fluorescence results demonstrated that TLP slightly disturbed the microenvironment of amino residues. Circular dichroism spectra showed that TLP affected the secondary structure of HSA. The theoretical and experimental results showed excellent agreement.