Evaluation of hybrid and pure DFT methods for the binding of novel ligands in the tyrosine hydroxylase enzyme

Abstract

The M06-2X, M06-L, and M06 functionals were used to evaluate the interaction energies of novel ligands in the TyrOH active site. TyrOH is the rate determining enzyme in the catecholamine-dopamine pathway, converting tyrosine to l-DOPA. The inhibition of TyrOH, however, reduces dopamine in the brain to undetectable levels (Spector et al., 1965). A crystal structure of the active site of tyrosine hydroxylase with a known inhibitor bound was obtained from the protein data bank (PDB ID: 2TOH) (Goodwill et al., 1998). In this work, dopaminergic derivatives, which could be potential treatments for Parkinson’s disease were inserted into the enzymatic active site in silico in order to test the strength of the interactions between the ligand and active site, to determine if any of these derivatives could be effective inhibitors. M06 and M06-2X are hybrid functionals, while M06-L is a pure DFT method; all of these functionals were used to optimize structures and to analyze interaction energies. The novel dopaminergic derivatives were optimized in the active site with implicit solvent with either M06-2X, M06-L, or M06 and 6-31G with relaxed amino acid side chains. Counterpoise corrected interaction energies between the ligands and protein were determined using the same DFT methods mentioned above with the 6-311+G∗ basis set. This work shows significant differences between the methods within the same complex. The analysis has also helped to determine promising ligands for the treatment of Parkinson’s disease that would not inhibit TyrOH.