The effects of ligand deprotonation on the binding selectivity of the phenylalanine hydroxylase active site

Abstract

There are many targets for dopaminergic molecules in the body; these molecules can activate or inhibit these targets with beneficial or detrimental effects. Phenylalanine hydroxylase (PheOH) is a tetradydrobiopterin-dependent monooxygenase that converts phenylalanine into tyrosine. Both phenylalanine and tyrosine are important components in the anabolism of dopamine. A deficiency of PheOH or inhibition of the enzyme can cause hyperphenylalaninemia, which gives rise to phenylketonuria (PKU), a disease that can cause severe cognitive side effects. A suite of dopaminergic derivatives has been developed to be tested in the PheOH active site. The inhibitory effectiveness of these dopaminergic derivatives on PheOH has been measured via in silico models, in which the interaction energies between each substrate and the enzymatic active site were calculated. A crystal-structure of the PheOH active site, with bound thienylalanine—a known inhibitor—was isolated from the Protein Data Bank (PDB ID: 1KW0). The positions of novel dopaminergic derivatives were optimized in the active site using M062X/6-31G with implicit solvation and with flexible amino acid side-chains. Interaction energies between the ligands and the protein were calculated using M062X with the 6–311+G* basis set. We report promising novel catechols that do not inhibit this enzyme. Results show deprotonation of the ligands by the active site can strongly affecting their binding strength, thus the pKas for all novel ligands were calculated and are reported.