Vladimir Vlatković1*, Saša Lazović1, Aleksandra Đukić-Vuković2, Milica Radan3, Bojan Marković4, Jelena Savić4, Zorica Vujić4 and Darija Obradović1
1Institute of Physics Belgrade, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
2Faculty of Technology and Metallurgy, University of Belgrade, Belgrade, Serbia
3Institute for the Study of Medicinal Plants “Dr. Josif Pančić”, Belgrade, Serbia
4Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
vlatkovic [at] ipb.ac.rs
Abstract
Molecular docking is used as a virtual screening approach that allows the prediction of ligand-receptor binding modes and ranking ligands. Human serum albumin (HSA) is a key transport protein responsible for the distribution of drugs and small bioactive molecules in the human body. HSA binding is important for the compound’s therapeutic potential. Phenolic compounds are recognised for their bioactive potential, including antioxidative, neuroprotective and antidiabetic activities.
The goal of the study was to determine the binding affinities of selected phenolic acids to Sudlow binding site I (warfarin binding site) within HSA and to describe intermolecular interactions governing the binding process. The receptor structure of HSA subdomain IIA containing Sudlow binding site I (PDB ID: 2BXD) and ligands (structurally related chlorogenic acid and isochlorogenic acid A, as well as reference ligand warfarin), were preprocessed before the docking study. The receptor grid box was generated with pinpoint accuracy to include warfarin binding site shape, size and properties. Molecular docking of selected phenolic compounds was performed using Glide molecular modeling software. This software performs docking by examining conformational, positional, and orientational degrees of freedom of ligands within a defined rigid receptor grid, while utilizing the Glide score function to rank binding affinities and visual generation of compound-HSA binding complex environment and interactions.
The results showed that chlorogenic acid (-6.335) and isochlorogenic acid A (-7.438) had similar binding affinity to warfarin (-7.866). Binding interactions include hydrophobic, hydrogen bond, and, in the case of chlorogenic acid, salt bridge interactions. Isochlorogenic acid features fewer hydrogen bond interactions, but is enclosed in a more hydrophobic cavity, and is less exposed to solvent than chlorogenic acid, indicating its stronger and more stable binding to HSA binding site I.
Molecular docking using Glide enabled fast, effective, high-accuracy analysis, showing that tested phenolic acids have comparable binding affinity and similar binding interactions to HSA binding site I as warfarin. The high accuracy of this method also showcased the influence that subtle structural differences play in the binding mechanism and positioning of ligands within the binding site. This approach proved its potential as a virtual screening method in bioactive compound studies.
Keywords: molecular docking. HSA. binding interactions
Acknowledgement: This research was supported by the Science Fund of the Republic of Serbia, GRANT No 13534, Proof of Concept – DIAMICA. The authors also acknowledge funding provided by the Institute of Physics Belgrade, National Institute of the Republic of Serbia, through the grant from the Ministry of Science, Technological Development, and Innovation of the Republic of Serbia