Skip to main content

Ligand-side tautomer enumeration and scoring for structure-based drug-design

Tautomeric rearrangements of a molecule lead to distinct equilibrated structural states of the same chemical compound that may differ significantly in molecular shape, surface, nature of functional groups, hydrogen-bonding pattern and other derived molecular properties [1]. Especially for the structure-based pharmacophore modeling of ligand-protein complexes [2], knowledge of the most favorable tautomeric ligand states may be crucial for the quality and correctness of the generated pharmacophore models and derived putative binding modes. We will present a ligand-side tautomer enumeration and ranking algorithm that considers both geometrical constraints imposed by the conformation of the bound ligand as well as intra- and inter-molecular energetic contributions to find the preferred tautomeric states of the ligand in the macromolecular environment of the binding-site. The presented tautomer ranking algorithm is based on scores that are derived solely from MMFF94 [39] energies (thus the method works for a wide range of organic molecules) and has proven to be able to top-rank known preferred tautomeric states of ligands in a series of investigated protein complexes.

References

  1. 1.

    Pospisil P, et al: J Recept Signal Transduct. 2003, 23: 361-371. 10.1081/RRS-120026975.

    CAS  Article  Google Scholar 

  2. 2.

    Wolber G, Langer T: J Chem Inf Model. 2005, 45: 160-169. 10.1021/ci049885e.

    CAS  Article  Google Scholar 

  3. 3.

    Halgren TA: J Comput Chem. 1996, 17: 490-519. 10.1002/(SICI)1096-987X(199604)17:5/6<490::AID-JCC1>3.0.CO;2-P.

    CAS  Article  Google Scholar 

  4. 4.

    Halgren TA: J Comput Chem. 1996, 17: 520-552. 10.1002/(SICI)1096-987X(199604)17:5/6<520::AID-JCC2>3.0.CO;2-W.

    CAS  Article  Google Scholar 

  5. 5.

    Halgren TA: J Comput Chem. 1996, 17: 553-586. 10.1002/(SICI)1096-987X(199604)17:5/6<553::AID-JCC3>3.0.CO;2-T.

    CAS  Article  Google Scholar 

  6. 6.

    Halgren TA, Nachbar RB: J Comput Chem. 1996, 17: 587-615.

    CAS  Google Scholar 

  7. 7.

    Halgren TA: J Comput Chem. 1996, 17: 616-651. 10.1002/(SICI)1096-987X(199604)17:5/6<616::AID-JCC5>3.0.CO;2-X.

    CAS  Article  Google Scholar 

  8. 8.

    Halgren TA: J Comput Chem. 1999, 20: 720-729. 10.1002/(SICI)1096-987X(199905)20:7<720::AID-JCC7>3.0.CO;2-X.

    CAS  Article  Google Scholar 

  9. 9.

    Halgren TA: J Comput Chem. 1999, 20: 730-748. 10.1002/(SICI)1096-987X(199905)20:7<730::AID-JCC8>3.0.CO;2-T.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Thomas Seidel.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Seidel, T., Wolber, G. Ligand-side tautomer enumeration and scoring for structure-based drug-design. J Cheminform 2, P32 (2010). https://doi.org/10.1186/1758-2946-2-S1-P32

Download citation

Keywords

  • Pharmacophore Model
  • Ranking Algorithm
  • Molecular Shape
  • Molecule Lead
  • Putative Binding