MP2//DFT calculations of interaction energies between acetaminophen and acetaminophen analogues and the aryl sulfotransferase active site

• Published in: Computational and theoretical chemistry 2013-03, Vol.1007, p.41-47
• Main Authors: DiGiovanni, Katherine M., Katherine Hatstat, A., Rote, Jennifer, Cafiero, Mauricio
• Format: Article
• Language: English
• Subjects: Acetaminophen; DFT; Hydrogen-bonds; MP2; Sulfotransferase
• ISSN: 2210-271X
• DOI: 10.1016/j.comptc.2012.12.004

Acetaminophen docked and optimized (BHandHLYP/3-21G) in the rigid (left) and flexible (right) aryl sulfotransferase active site. [Display omitted] ► We examine the interactions of acetaminophen-like molecules with aryl sulfotransferase. ► Competition for the active site of sulfotransferase may increase the toxicity of acetaminophen. ► MP2 was used to calculate the interactions between the ligands and the enzyme. ► Results agree with previous experimental results. Paracetamol, or acetaminophen, is a commonly used analgesic and antipyretic. Cresols such as p-cresol, o-cresol, and m-cresol can compete with acetaminophen for metabolism via several pathways, including via sulfation by aryl sulfotransferase. We have applied the MP2 method to study the interaction of acetaminophen and these cresol analogues with the active site of aryl sulfotransferase. Docking and BHandHLYP/6-31G optimization were used to find the structures of the ligand–protein complexes assuming a static active site. Interaction energies between the ligands and each of the amino acids in the active site were calculated using MP2 with a basis set of 6-311+g*. Further optimizations were then performed to allow flexibility of the amino acid residue side-chains in the active site and interaction energies were calculated for these complexes as well. p-Cresol is shown to compete with acetaminophen for this metabolic pathway, in agreement with experiment. We also show that m-cresol should be competitive for this metabolic pathway.