Ab initio study of electronic interaction energies and desolvation energies for dopaminergic ligands in the catechol-O-methyltransferase active site

作者：Hatstat A Katherine; Morris Mallory; Peterson Larryn W; Cafiero Mauricio^*

来源：Computational and Theoretical Chemistry, 2016, 1078: 146-162.

DOI：10.1016/j.comptc.2016.01.003

• DFT
• MP2
• COMT
• Dopamine
• Desolvation
• Interaction

Catechol-O-methyltransferase (COMT) deactivates dopamine and other catecholic substrates via the methylation of a hydroxyl group. The targeted inhibition of COMT can prevent premature metabolism of both endogenous and exogenous ligands; for example, it can prolong the effectiveness of L-DOPA treatments for Parkinson's disease. The inhibitory ability of a suite of dopaminergic derivatives against COMT has been studied using electronic interaction energies between each ligand and the enzymatic active site as well as desolvation energies for each ligand. A crystal structure of the COMT active site in complex with a known COMT inhibitor, BIA 8-176, was isolated from the Protein Data Bank (PDB ID: 2CL5). The positions of a suite of dopaminergic derivatives in this same active site were optimized using M062X/6-31G with three different model chemistries: in vacuo with rigid amino acid side chains, with implicit solvation and rigid amino acid side chains, and with implicit solvation and flexible amino acid side chains. Electronic interaction energies between the ligands and the active site residues were calculated for each model using M06L and MP2 with the 6-311+G* basis set. Ligands with a nitrile substituent were favored over other substituents in vacuo, but this preference was not retained when the same ligands were optimized with implicit solvation; the preference was regained when using implicit solvation and a relaxed active site. Desolvation energies of the ligands were calculated using a series of hydration shells (n = 7, 9,11 and 13) with M062X and the aug-cc-pvdz, cc-pvdz, and cc-pvtz basis sets. Ligands with carboxyl and nitro substituents exhibited the least favorable desolvation energies, whereas ligands with the nitrile substituents exhibited the most favorable desolvation energies.

• 出版日期2016-2-15