From building blocks of proteins to drugs: A quantum chemical study on structure-property relationships of phenylalanine, tyrosine and dopa

Density functional theory and ab initio methods have been employed to address the impacts of hydroxyl (OH) group substitutions on the physico-chemical properties of levodopa (or l-dopa) against the natural amino acids, phenylalanine and tyrosine. l-dopa, which is an important therapeutic drug for Parkinson's disease, shares structural homology with the amino acids, whose structures differ only by OH substitutions in their phenyl side chains. It is revealed that the backbone geometries of the aromatic molecules do not show apparent OH-dependent differences; however, their other molecular-level properties, such as molecular dipole moment, electronic properties and aromaticity, change significantly. The core binding energy spectra indicate that the atom sites that undergo modifications exhibit large energy shifts, so as to accommodate the changes in the intra-molecular chemical environment of the molecules. The binding energies of the modified C 1s sites in the molecules shift as much as 1.8 eV, whereas the electronic changes in their O 1s spectra happen in the higher energy region (ca. 536 eV). The valence spectra provide enhanced insights into the reactivity and chemical properties of the aromatic molecules. The impacts of OH moieties on the valence spectra are predominantly focussed in the energy band <16 eV, where the frontier molecular orbitals display much reorganization and energy shifts from the amino acids to l-dopa. Of the three molecules, l-dopa also has the least HOMO-LUMO energy gap, which can readily explain its proactivity as a drug compound. Furthermore, the nuclear independent chemical shift calculations suggest that l-dopa also has more aromaticity features than those of the amino acids. The OH groups, therefore, play a more prominent role in shaping the physico-chemical properties of l-dopa, which significantly improve its drug potency.