Skip to main content
SpringerLink
Log in

Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

Generating the appropriate protonation states of drug-like molecules in solution is important for success in both ligand- and structure-based virtual screening. Screening collections of millions of compounds requires a method for determining tautomers and their energies that is sufficiently rapid, accurate, and comprehensive. To maximise enrichment, the lowest energy tautomers must be determined from heterogeneous input, without over-enumerating unfavourable states. While computationally expensive, the density functional theory (DFT) method M06-2X/aug-cc-pVTZ(-f) [PB-SCRF] provides accurate energies for enumerated model tautomeric systems. The empirical Hammett–Taft methodology can very rapidly extrapolate substituent effects from model systems to drug-like molecules via the relationship between pKT and pKa. Combining the two complementary approaches transforms the tautomer problem from a scientific challenge to one of engineering scale-up, and avoids issues that arise due to the very limited number of measured pKT values, especially for the complicated heterocycles often favoured by medicinal chemists for their novelty and versatility. Several hundreds of pre-calculated tautomer energies and substituent pKa effects are tabulated in databases for use in structural adjustment by the program Epik, which treats tautomers as a subset of the larger problem of the protonation states in aqueous ensembles and their energy penalties. Accuracy and coverage is continually improved and expanded by parameterizing new systems of interest using DFT and experimental data. Recommendations are made for how to best incorporate tautomers in molecular design and virtual screening workflows.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Comer J, Tam K (2001) In: Testa B, van de Waterbeemd H, Folkers G, Guy R (eds) Pharmacokinetic optimization in drug research: biological, physicochemical, and computational strategies. Wiley, Weinheim, pp 275–304

    Chapter  Google Scholar 

  2. Pospisil P, Ballmer P, Scapozza L, Folkers G (2003) Tautomerism in computer-aided drug design. J Recept Signal Transduct Res 23(4):361–371

    Article  CAS  Google Scholar 

  3. Rester U (2008) From virtuality to reality—virtual screening in lead discovery and lead optimization: a medicinal chemistry perspective. Curr Opin Drug Discov Dev 11(4):559–568

    CAS  Google Scholar 

  4. Shelley JC, Cholleti A, Frye LL, Greenwood JR, Timlin MR, Uchimaya M (2007) Epik: a software program for pK(a) prediction and protonation state generation for drug-like molecules. J Comput Aided Mol Des 21(12):681–691

    Article  CAS  Google Scholar 

  5. Epik, v2.0 (2009) Schrödinger, Inc., New York

  6. LigPrep, v2.3 (2009) Schrödinger, Inc., New York

  7. Milletti F, Storchi L, Sforna G, Cross S, Cruciani G (2009) Tautomer enumeration and stability prediction for virtual screening on large chemical databases. J Chem Inf Model 49(1):68–75

    Article  CAS  Google Scholar 

  8. Oellien F, Cramer J, Beyer C, Ihlenfeldt WD, Selzer PM (2006) The impact of tautomer forms on pharmacophore-based virtual screening. J Chem Inf Model 46(6):2342–2354

    Article  CAS  Google Scholar 

  9. Haranczyk M, Gutowski M (2007) Quantum mechanical energy-based screening of combinatorially generated library of tautomers. TauTGen: a tautomer generator program. J Chem Inf Model 47(2):686–694

    Article  CAS  Google Scholar 

  10. Pisklak M, Maciejewska D, Herold F, Wawer I (2003) Solid state structure of coumarin anticoagulants: warfarin and sintrom. 13C CPMAS NMR and GIAO DFT calculations. J Mol Struct 649(1–2):169–176

    Article  CAS  Google Scholar 

  11. Zhang J, Yang PL, Gray NS (2009) Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9(1):28–39

    Article  Google Scholar 

  12. Pauling L (1960) The nature of the chemical bond, 3rd edn. Cornell University Press, Ithaca

    Google Scholar 

  13. Elguero J, Katritzky AR, Marzin C, Linda P (1976) The tautomerism of heterocycles. Academic Press, New York

    Google Scholar 

  14. Rauhut G (2002) Recent advances in computing heteroatom-rich five and six-membered ring systems. Adv Heterocycl Chem 81:2–85

    Google Scholar 

  15. Bryantsev VS, Diallo MS, van Duin ACT, Goddard III WA (2009) Evaluation of B3LYP, X3LYP, and M06-class density functionals for predicting the binding energies of neutral, protonated, and deprotonated water clusters. J Chem Theory Comput 5(4):1016–1026

    Article  CAS  Google Scholar 

  16. Harding ME, Metzroth T, Gauss J, Auer AA (2008) Parallel calculation of CCSD and CCSD(T) analytic first and second derivatives. J Chem Theory Comput 4(1):64–74

    Article  CAS  Google Scholar 

  17. Fabian WMF (1991) Tautomeric equilibria of heterocyclic molecules. A test of the semiempirical AM1 and MNDO-PM3 methods. J Comput Chem 12(1):17–35

    Article  CAS  Google Scholar 

  18. Stewart JJP (2007) Optimization of parameters for semiempirical methods V: modification of NDDO approximations and application to 70 elements. J Mol Model 13(12):1173–1213

    Article  CAS  Google Scholar 

  19. Tirado-Rives J, Jorgensen WL (2008) Performance of B3LYP density functional methods for a large set of organic molecules. J Chem Theory Comput 4(2):297–306

    Article  CAS  Google Scholar 

  20. Cramer CJ, Truhlar DG (1993) Correlation and solvation effects on heterocyclic equilibria in aqueous solution. J Am Chem Soc 115(19):8810–8817

    Article  CAS  Google Scholar 

  21. Zhao Y, Truhlar DG (2007) The M06 suite of density functionals for main group thermochemistry, kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06 functionals and twelve other functionals. Theor Chem Acc 120:215–241

    Article  Google Scholar 

  22. Jaguar, v7.6 (2009) Schrödinger, Inc., New York

  23. Zhao Y, Truhlar DG (2008) Exploring the limit of accuracy of the global hybrid meta density functional for main-group thermochemistry, kinetics, and noncovalent interactions. J Chem Theory Comput 4(11):1849–1868

    Article  CAS  Google Scholar 

  24. Frydenvang K, Greenwood JR, Vogensen SB, Brehm L (2002) Structural features of ATPA and Thio-ATPA—potent and selective GluR5 receptor agonists. Crystal structure determinations and quantum chemical calculations. Struct Chem 13(5–6):479–490

    Article  CAS  Google Scholar 

  25. Ahlquist MSG, Kozuch S, Shaik S, Tanner DA, Norrby P-O (2006) On the performance of continuum solvation models for the solvation energy of small anions. Organometallics 25(1):45–47

    Article  CAS  Google Scholar 

  26. Nielsen PA, Jaroszewski JW, Norrby PO, Liljefors T (2001) An NMR and ab initio quantum chemical study of acid-base equilibria for conformationally constrained acidic alpha-amino acids in aqueous solution. J Am Chem Soc 123(9):2003–2006

    Article  CAS  Google Scholar 

  27. Nielsen PA, Jaroszewski JW, Norrby PO, Liljefors T (2002) Conformational analysis of cyclic acidic alpha-amino acids in aqueous solution—an evaluation of different continuum hydration models. Unpublished data and PhD thesis, University of Copenhagen

  28. Marenich AV, Cramer CJ, Truhlar DG (2009) Performance of SM6, SM8, and SMD on the SAMPL1 test set for the prediction of small-molecule solvation free energies. J Phys Chem B 113(14):4538–4543

    Article  CAS  Google Scholar 

  29. Katritzki AR, Lagowski J (1963) Adv Heterocycl Chem 1:339

    Article  Google Scholar 

  30. Katritzky AR, Øksne S, Boulton AJ (1962) The tautomerism of heteroaromatic compounds with five-membered rings—III: further isoxazol-5-ones. Tetrahedron 18(6):777–790

    Article  CAS  Google Scholar 

  31. Le HT, Lamb JG, Franklin MR (1998) Drug metabolizing enzyme induction by benzoquinolines, acridine, and quinacrine; tricyclic aromatic molecules containing a single heterocyclic nitrogen. J Biochem Toxicol 11(6):297–303

    Article  Google Scholar 

  32. Harvey RG (1991) Aromatic hydrocarbons: chemistry and carcinogenicity. Cambridge University Press, Cambridge

    Google Scholar 

  33. Perrin DD, Dempsy B, Sergeant EP (1981) pKa prediction for organic acids and bases. Chapman and Hall, London

    Google Scholar 

  34. Gordon A, Katritzky AR, Roy SK (1968) Tautomeric pyridines. Part X. Effects of substituents on pyridone–hydroxypyridine equilibria and pyridone basicity. J Chem Soc B 1968:556–561

    Article  Google Scholar 

  35. ACD/PhysChem Suite, v12.0 (2009) Advanced Chemistry Development, Inc., Toronto

  36. Pallas pKalc Net., v2.0 (2009) Compudrug International Inc., Sedona

  37. Hilal S, Karickhoff SW, Carreira LA (1995) A rigorous test for SPARC’s chemical reactivity models: estimation of more than 4300 ionization pKa’s. Quant Struct Act Relatsh 14:348–355

    Article  CAS  Google Scholar 

  38. Liao C, Nicklaus MC (2009) Comparison of nine programs predicting pK(a) values of pharmaceutical substances. J Chem Inf Model 49(12):2801–2812

    Article  CAS  Google Scholar 

  39. Klicic J, Friesner RA, Liu S-Y, Guida WC (2002) Accurate prediction of acidity constants in aqueous solution via density functional theory and self-consistent reaction field methods. J Phys Chem A 106(7):1327–1335

    Article  CAS  Google Scholar 

  40. Martin YC (2009) Let’s not forget tautomers. J Comput-Aided Mol Des 23(10):673–704

    Google Scholar 

  41. Guimaraes CR, Cardozo M (2008) MM-GB/SA rescoring of docking poses in structure-based lead optimization. J Chem Inf Model 48(5):958–970

    Article  CAS  Google Scholar 

  42. Fogolari F, Brigo A, Molinari H (2003) Protocol for MM/PBSA molecular dynamics simulations of proteins. Biophys J 85(1):159–166

    Article  CAS  Google Scholar 

  43. Furet P, Meyer T, Strauss A, Raccuglia S, Rondeau JM (2002) Structure-based design and protein X-ray analysis of a protein kinase inhibitor. Bioorg Med Chem Lett 12(2):221–224

    Article  CAS  Google Scholar 

  44. Repasky M (2009) Enhancing Glide Enrichment Using Epik Ionization and Tautomeric State Penalties. Schrodinger Quaterly Newsletter, August

  45. Prime-X, v1.6 (2009) Schrödinger, Inc., New York

  46. Brandstetter H, Grams F, Glitz D, Lang A, Huber R, Bode W, Krell HW, Engh RA (2001) The 1.8-A crystal structure of a matrix metalloproteinase 8-barbiturate inhibitor complex reveals a previously unobserved mechanism for collagenase substrate recognition. J Biol Chem 276(20):17405–17412

    Article  CAS  Google Scholar 

  47. Temperini C, Cecchi A, Scozzafava A, Supuran CT (2009) Carbonic anhydrase inhibitors. Comparison of chlorthalidone and indapamide X-ray crystal structures in adducts with isozyme II: when three water molecules and the keto-enol tautomerism make the difference. J Med Chem 52(2):322–328

    Article  CAS  Google Scholar 

  48. Yan X, Hollis T, Svinth M, Day P, Monzingo AF, Milne GW, Robertus JD (1997) Structure-based identification of a ricin inhibitor. J Mol Biol 266(5):1043–1049

    Article  CAS  Google Scholar 

  49. Kalliokoski T, Salo HS, Lahtela-Kakkonen M, Poso A (2009) The effect of ligand-based tautomer and protomer prediction on structure-based virtual screening. J Chem Inf Model 49(12):2742–2748

    Article  CAS  Google Scholar 

  50. Glide, v5.5 (2009) Schrödinger, Inc., New York

  51. Rejnek J, Hobza P (2007) Hydrogen-bonded nucleic acid base pairs containing unusual base tautomers: complete basis set calculations at the MP2 and CCSD(T) levels. J Phys Chem B 111(3):641–645

    Article  CAS  Google Scholar 

  52. Shukla M, Leszcynski J (2008) Radiation induced molecular phenomena in nucleic acids: a comprehensive theoretical and experimental analysis. Springer, Berlin

    Book  Google Scholar 

  53. Canvas, v1.2 (2009) Schrödinger, Inc., New York

Download references

Author information

Authors and Affiliations

  1. Schrödinger, L.L.C., 120 West 45th St., 17th Floor, Tower 45, New York, NY, 10035-4041, USA

    Jeremy R. Greenwood

  2. Schrödinger, L.L.C., Suite 1300, 101 SW Main Street, Portland, OR, 97204, USA

    David Calkins, Arron P. Sullivan & John C. Shelley

Authors
  1. Jeremy R. Greenwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Calkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arron P. Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John C. Shelley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeremy R. Greenwood.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Greenwood, J.R., Calkins, D., Sullivan, A.P. et al. Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution. J Comput Aided Mol Des 24, 591–604 (2010). https://doi.org/10.1007/s10822-010-9349-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-010-9349-1

Keywords

Search

Navigation