In silico mechanistic profiling to probe small molecule binding to sulfotransferases

PLoS One. 2013 Sep 6;8(9):e73587. doi: 10.1371/journal.pone.0073587. eCollection 2013.


Drug metabolizing enzymes play a key role in the metabolism, elimination and detoxification of xenobiotics, drugs and endogenous molecules. While their principal role is to detoxify organisms by modifying compounds, such as pollutants or drugs, for a rapid excretion, in some cases they render their substrates more toxic thereby inducing severe side effects and adverse drug reactions, or their inhibition can lead to drug-drug interactions. We focus on sulfotransferases (SULTs), a family of phase II metabolizing enzymes, acting on a large number of drugs and hormones and showing important structural flexibility. Here we report a novel in silico structure-based approach to probe ligand binding to SULTs. We explored the flexibility of SULTs by molecular dynamics (MD) simulations in order to identify the most suitable multiple receptor conformations for ligand binding prediction. Then, we employed structure-based docking-scoring approach to predict ligand binding and finally we combined the predicted interaction energies by using a QSAR methodology. The results showed that our protocol successfully prioritizes potent binders for the studied here SULT1 isoforms, and give new insights on specific molecular mechanisms for diverse ligands' binding related to their binding sites plasticity. Our best QSAR models, introducing predicted protein-ligand interaction energy by using docking, showed accuracy of 67.28%, 78.00% and 75.46%, for the isoforms SULT1A1, SULT1A3 and SULT1E1, respectively. To the best of our knowledge our protocol is the first in silico structure-based approach consisting of a protein-ligand interaction analysis at atomic level that considers both ligand and enzyme flexibility, along with a QSAR approach, to identify small molecules that can interact with II phase dug metabolizing enzymes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arylsulfotransferase / chemistry
  • Arylsulfotransferase / metabolism
  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Protein Binding
  • Protein Structure, Tertiary*
  • Quantitative Structure-Activity Relationship
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism
  • Sulfotransferases / chemistry*
  • Sulfotransferases / metabolism
  • Thermodynamics
  • Xenobiotics / chemistry*
  • Xenobiotics / metabolism


  • Ligands
  • Small Molecule Libraries
  • Xenobiotics
  • Sulfotransferases
  • Arylsulfotransferase
  • SULT1A1 protein, human
  • monoamine-sulfating phenol sulfotransferase
  • estrone sulfotransferase

Grants and funding

V.Y.M. was supported by the doctoral school ‘MTCE’ at the Universities Paris Descartes and Paris Diderot. P.C. was supported by Genopole (ATIGE grant) and Agence Nationale de la Recherche. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.