Vladimir Vlatković1*, Katarzyna Wicha-Komsta2, Tomasz Kocki2, Łukasz Komsta3, Saša Lazović4 and Darija Obradović4
1Institute of Physics Belgrade, National Institute of the Republic of Serbia, University of Belgrade
2Institute of Medical Sciences, Faculty of Medicine, The John Paul II Catholic University of Lublin, Lublin, Poland
3Faculty of Pharmacy, Medical University of Lublin, Lublin, Poland
4Institute of Physics Belgrade, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
vlatkovic [at] ipb.ac.rs
Abstract
Inhibition of the cyclooxygenase-2 (Cox-2) enzyme is important for the mediation of inflammation. The binding of inhibitors to the Cox-2 active site blocks the conversion of arachidonic acid into pro-inflammatory prostaglandins, thus reducing inflammation. This is a well-established and important direction in the development of anti-inflammatory substances. Coumarin derivatives are known to possess Cox-2 inhibitory potential.
The goal of this study is to examine the binding affinity of selected coumarin derivatives to the Cox-2 active site and to gain insight into important molecular interactions governing the binding, using molecular docking. A parallel study was performed for celecoxib, a well-known and effective Cox-2 selective inhibitor, for comparison. The structure of the Cox-2 active site (PDB ID: 3LN1) was obtained from the RCSB PDB database. Target protein structure and ligand molecules were preprocessed, optimized and refined before the docking study. Amino acid residues key to binding of celecoxib to the active site were chosen for the generation of the receptor grid box: His 75, Val 102, Arg 106, Gln 178, Val 335, Leu 338, Ser 339, Tyr 341, Leu 345, Phe 367, Leu 370, Tyr 371, Trp 373, Arg 499, Phe 504, Val 509, Ser 516, and Leu 517. The docking study was performed using the Glide molecular modeling tool. Ligand binding affinity was based on the Glide scoring function that accounts for Coulomb-van der Waals energies, hydrogen bond interactions and lipophilic interactions for high-accuracy assessment of binding strength.
The results indicated that the tested coumarin derivatives had a binding affinity to the active site defined in the docking study, similar to celecoxib. Binding affinities are as follows: umbelliferone> 4-metoxyumbelliferone> celecoxib> 7-metoxycoumarin> coumarin> 6,7-dimetoxycoumarin> 6,7-dixydroxycoumarin> 3,3-methylen-bis-hydroxycoumarin. Visualization of the binding complex showed that the studied ligands were located in the binding site consisting of large, aromatic, hydrophobic, as well as positively charged and polar amino acid residues. Tested coumarin derivatives interacted primarily by hydrogen bonds, hydrophobic contacts and Pi-cation (Pi-Pi for celecoxib) interactions. The applied docking method represents a fast and precise approach that can be used for the preliminary screening of novel coumarin derivatives as potential Cox-2 inhibitors.
Keywords: Cox-2 inhibition. coumarin derivatives. docking