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

Abstract

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 substituent 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.

The effects of ligand charge, orientation and size on the binding of potential inhibitors for aldehyde dehydrogenase

“…The molecule suites that were tested in this study were designed based on previous work in this group 3,4,5 . The LP-suite (Fig.…”

“…The targeted, reversible inhibition of the ALDH enzyme may help to prolong the effectiveness of L-DOPA, resulting in a net increase in pharmacological efficiency for L-DOPA. This work and related work in our lab has the goal of finding a drug candidate that will inhibit enzymes in the dopamine pathway, such as aldehyde dehydrogenase (ALDH), while keeping the enzymes in the dopamine synthesis pathway active 3,4,5 .…”

“…M062X was also used for all interaction energy calculations, as previous work has shown that it is among the most accurate DFT methods calculating non-covalent interaction energies 3 . The un-modified M062X functional takes into account weak forces, such as induction and dispersion (see the work of Zhao and Trulhar 10,11 ) and has been tested against training sets that include weak non-covalent interactions; it does not require additional dispersion, as is shown in our own previous work [3][4][5] . The current work is based on the differential positioning of ligands in the active site and comparison with the calculated interaction energies of previously tested inhibitors CM026, CM053, and CM037 (Fig.…”

Twenty years of exceptional success: The molecular education and research consortium in undergraduate computational chemistry (MERCURY)

“…The faculty published 2 peer‐reviewed books, [ 238,239 ] 9 peer‐reviewed book chapters, [ 240–248 ] and 115 peer‐reviewed research papers. [ 249–363 ] This comes to 1.6 peer‐reviewed products/faculty/year during the 3‐year grant period, which is 3.2 times the rate of publication for natural science faculty at PUIs. [ 46 ]…”

“…They investigate acetaminophen metabolism by a sulfotransferase enzyme (SULT1A3), [ 197 ] using an active site model from a crystal structure [ 382 ] using DFT and MP2 methods. Working with an experimental collaborator, they expanded this study to how a suite of catecholaminic and catecholic molecules interacts with SULT1A3, [ 228,229 ] SULT1A1, catechol‐ o ‐methyltransferase, [ 260 ] phenylalanine hydroxylase, [ 354 ] tyrosine hydroxylase, [ 308 ] and other enzymes/receptors. They are also working on the discovery of inhibitors for the LpxC enzyme for Gram‐negative bacteria.…”