We have studied the substrate selectivity of a number of known bioactive ligands in sulfotransferase enzyme (SULT1A3) and catechol-o-methyltransferase (COMT) by identifying important protein-ligand interactions in the active-sites through electronic structure calculations. SULT1A3 is responsible for activating and improving the solubility of catecholamines while COMT deactivates catecholamines. Understanding how ligands behave in both of these enzymes leads to a greater understanding of the fate of dopaminergic molecules in the body. The SULT1A3 and COMT enzymes catalyze the addition of a sulfate group and a methyl group, respectively, to a variety of small molecules, including catecholaminergic molecules. Crystal structures of the SULT1A3 (PBD ID 2A3R) and COMT (PDB ID 2CL5) enzyme active sites were isolated from the Protein Data Bank. A suite of molecules with known activity in COMT were chosen from PubChem and their positions in each active site were optimized using M062X/6-31G including implicit solvation and using flexible amino acid residues. Interaction energies between the ligands and the proteins were calculated using M062X with the 6-311+G* basis set. Calculations have shown that molecules active in COMT also show a promise of strong activity in SULT1A3. The 5-carboxyl-3-nitrocatechol and 4-acetyl-3-nitrocatechol molecules show greater affinity for COMT and lower affinity for SULT1A3. In addition, multiple QSAR models for ligand binding in COMT have been developed and show promising results.

DFT analysis of the selectivity of known bioactive ligands in the sulfotransferase and catechol-o-methyltransferase enzymes

253rd National Meeting (2017)

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