Quantum chemical analysis of ligand binding in the dopa decarboxylase active site and in silico design of novel ligands with improved active site binding affinity

Abstract

Serotonin and dopamine are two neurotransmitters that are crucial to brain activity. An imbalance of serotonin and dopamine in the brain can lead to a variety of disorders such as serotonin syndrome or Parkinson’s disease, respectively. DOPA decarboxylase is the enzyme that catalyzes the final step in the synthesis of serotonin and dopamine; inhibitors of and mutations to the active site of DOPA decarboxylase may alter the catalytic activity of the enzyme. Previously, the author has studied how mutations to the DOPA decarboxylase active site affect the binding of the ligand pyridoxal phosphate (an enzyme cofactor used in serotonin and dopamine synthesis) and carbiDOPA (a Parkinson's drug). In this work, the author performs a high accuracy quantitative study of how 5-HT and L-DOPA (pre-cursors to serotonin and dopamine), as well as several inhibitors of DOPA decarboxylase (methylDOPA, carbiDOPA, and benserazide) bind to the active site. Using the data concerning the binding of these ligands, the author has designed and docked novel ligands with optimal binding affinity, which may competitively inhibit the activity of the enzyme, thus preventing production of serotonin and dopamine. Interaction energies between all docked ligands and residues in the enzyme active site are calculated vii using counterpoise-corrected MP2 and Density Functional Theory calculations. The results for two DOPA decarboxylase inhibitors, carbiDOPA and methylDOPA, agree with experimental evidence that they are potent inhibitors, and the results for the author’s newly designed ligands show that they may be potent inhibitors as well.