MOLECULAR DOCKING AND MOLECULAR DYNAMICS STUDIES OF THE INTERACTION BETWEEN COUMARIN-NEUROTRANSMITTER DERIVATIVES AND CARBONIC ANHYDRASE IX

Novel biologically active compounds can be obtained by the structural modification of coumarins. In this contribution, five new derivatives of 4-hydroxycoumarin with tyramine, octopamine, norepinephrine, 3-methoxytyramine, and dopamine were obtained. Their structures were optimized based on the previously obtained crystal structure of the 4-hydroxycoumarin-dopamine derivative. The special emphasis was put on the effect of various substituents on the structure of obtained compounds and intramolecular interactions governing the stability. To investigate their possible antitumor activity, molecular docking and molecular dynamics simulations were performed with Carbonic anhydrase, a prognostic factor in several cancers, and compared to the native ligand, 5-acetamido-1,3,4-thiadiazole- 2-sulfonamide. The results have shown that all of the coumarin-neurotransmitter derivatives bind to the active pocket of protein with the binding energies higher than for the native ligand. The main contributions to the binding energies were discussed. The Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and Radius of gyration (Rg), as results of MD simulations, were used to predict the activity of compounds towards chosen protein. The highest MD binding energies were obtained for the derivatives with dopamine and 3-methoxytyramine, with the van der Waals interaction and hydrogen bonds being the most important contributors.