Skip to main content
SpringerLink
Log in

A binding mode hypothesis for prothioconazole binding to CYP51 derived from first principles quantum chemistry

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

Abstract

In order to assess safety and efficacy of small molecule drugs as well as agrochemicals, it is key to understanding the nature of protein–ligand interaction on an atomistic level. Prothioconazole (PTZ), although commonly considered to be an azole-like inhibitor of sterol 14-α demethylase (CYP51), differs from classical azoles with respect to how it binds its target. The available evidence is only indirect, as crystallographic elucidation of CYP51 complexed with PTZ have not yet been successful. We derive a binding mode hypothesis for PTZ binding its target, compare to DPZ, a triazole-type metabolite of PTZ, and set our findings into context of its biochemistry and spectroscopy. Quantum Theory of Atoms in Molecules (QTAIM) analysis of computed DFT electron densities is used to qualitatively understand the topology of binding, revealing significant differences of how R- and S-enantiomers are binding and, in particular, how the thiozolinthione head of PTZ binds to heme compared to DPZ’s triazole head. The difference of binding enthalpy is calculated at coupled cluster (DLPNO-CCSD(T)) level of theory, and we find that DPZ binds stronger to CYP51 than PTZ by more than ΔH ~ 11 kcal/mol.

Graphic abstract

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

Scheme 1
Scheme 2
Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Stenzel K, Vors JP (2019) Mod Crop Prot Compd 2:797–844

    CAS  Google Scholar 

  2. CropLife International A.I.S.B.L., B. Fungicide Resistance Action Commitee. http://www.frac.info/publications

  3. Sono M, Roach MP, Coulter ED, Dawson JH (1996) Chem Rev 96(7):2841–2888

    Article  CAS  Google Scholar 

  4. Harris D, Loew G, Waskell L (1998) J Am Chem Soc 120(18):4308–4318

    Article  CAS  Google Scholar 

  5. Schöneboom JC, Thiel W (2004) J Phys Chem B 108(22):7468–7478

    Article  Google Scholar 

  6. Balding PR, Porro CS, McLean KJ, Sutcliffe MJ, Maréchal J-D, Munro AW, Visser SPD (2008) J Phys Chem A 112(50):12911–12918

    Article  CAS  Google Scholar 

  7. Kohn W (1999) Rev Mod Phys 71(5):1253–1266

    Article  CAS  Google Scholar 

  8. Hellpointer E, Borchers H (2004) Pflanzenschutz Nachrichten Bayer 57:163–180

    Google Scholar 

  9. Kuck K-H, Justus K (2004) Pflanzenschutz Nachrichten Bayer 57:207–224

    Google Scholar 

  10. Warrilow AG, Parker JE, Kelly DE, Kelly SL (2013) Antimicrob Agents Chemother 57(3):1352–1360

    Article  CAS  Google Scholar 

  11. Dimopoulou M, Verhoef A, Gomes CA, van Dongen CW, Rietjens IMCM, Piersma AH, van Ravenzwaay B (2018) Toxicol Lett 286:10–21

    Article  CAS  Google Scholar 

  12. Parker JE, Warrilow AGS, Cools HJ, Martel CM, Nes WD, Fraaije BA, Lucas JA, Kelly DE, Kelly SL (2011) Appl Environ Microbiol 77(4):1460–1465

    Article  CAS  Google Scholar 

  13. Parker JE, Warrilow AGS, Cools HJ, Fraaije BA, Lucas JA, Rigdova K, Griffiths WJ, Kelly DE, Kelly SL (2013) Appl Environ Microbiol 79(5):1639–1645

    Article  CAS  Google Scholar 

  14. Yoshida Y, Aoyama Y (1984) J Biol Chem 259(3):1655–1660

    Article  CAS  Google Scholar 

  15. Tyndall JDA, Sabherwal M, Sagatova AA, Keniya MV, Negroni J, Wilson RK, Woods MA, Tietjen K, Monk BC (2016) PLoS ONE 11(12):e0167485

    Article  Google Scholar 

  16. Caldararu O, Olsson MA, Riplinger C, Neese F, Ryde U (2017) J Comput Aided Mol Des 31(1):87–106

    Article  CAS  Google Scholar 

  17. Brandenburg JG, Bannwarth C, Hansen A, Grimme S (2018) J Chem Phys 148(6):064104

    Article  Google Scholar 

  18. Schrödinger (2018) Maestro, Schrödinger Release 2018-1; Schrödinger, LLC, New York, NY

  19. Frank N (2018) Wiley Interdiscip Rev 8(1):e1327

    Google Scholar 

  20. Becke AD (1988) Phys Rev A 38(6):3098–3100

    Article  CAS  Google Scholar 

  21. Weigend F (2006) Phys Chem Chem Phys 8(9):1057–1065

    Article  CAS  Google Scholar 

  22. Weigend F, Ahlrichs R (2005) Phys Chem Chem Phys 7(18):3297–3305

    Article  CAS  Google Scholar 

  23. Grimme S, Antony J, Ehrlich S, Krieg H (2010) J Chem Phys 132(15):154104

    Article  Google Scholar 

  24. Stefan G, Stephan E, Lars G (2011) J Comput Chem 32(7):1456–1465

    Article  Google Scholar 

  25. Dolg M, Wedig U, Stoll H, Preuss H (1987) J Chem Phys 86(2):866–872

    Article  CAS  Google Scholar 

  26. O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR (2011) J Cheminform 3(1):33

    Article  Google Scholar 

  27. O’Boyle NM, Vandermeersch T, Flynn CJ, Maguire AR, Hutchison GR (2011) J Cheminform 3(1):8

    Article  Google Scholar 

  28. Halgren TA (1996) J Comput Chem 17(5–6):490–519

    Article  CAS  Google Scholar 

  29. Riplinger C, Neese F (2013) J Chem Phys 138(3):034106

    Article  Google Scholar 

  30. Riplinger C, Pinski P, Becker U, Valeev EF, Neese F (2016) J Chem Phys 144(2):024109

    Article  Google Scholar 

  31. Riplinger C, Sandhoefer B, Hansen A, Neese F (2013) J Chem Phys 139(13):134101

    Article  Google Scholar 

  32. Hellweg A, Hättig C, Höfener S, Klopper W (2007) Theoret Chem Acc 117(4):587–597

    Article  CAS  Google Scholar 

  33. Hansen A, Bannwarth C, Grimme S, Petrović P, Werlé C, Djukic J-P (2014) ChemistryOpen 3(5):177–189

    Article  CAS  Google Scholar 

  34. Sparta M, Retegan M, Pinski P, Riplinger C, Becker U, Neese F (2017) J Chem Theory Comput 13(7):3198–3207

    Article  CAS  Google Scholar 

  35. Kruse H, Grimme S (2012) J Chem Phys 136(15):154101

    Article  Google Scholar 

  36. Keith TA (2017) AIMAll, Version 17.11.14; TK Gristmill Software, Overland Park KS, USA

  37. Wolfram Research, I (2019) Mathematica. Wolfram Research Inc, Champaign

    Google Scholar 

  38. Kosata B, Danne R (2010) BKChem

  39. Catalan J, Claramunt RM, Elguero J, Laynez J, Menendez M, Anvia F, Quian JH, Taagepera M, Taft RW (1988) J Am Chem Soc 110(13):4105–4111

    Article  CAS  Google Scholar 

  40. Meot-Ner M, Liebman JF, Del Bene JE (1986) J Organ Chem 51(7):1105–1110

    Article  CAS  Google Scholar 

  41. Groom CR, Bruno IJ, Lightfoot MP, Ward SC (2016) Acta Crystallogr Sect B 72(2):171–179

    Article  CAS  Google Scholar 

  42. Beck ME, Gutbrod O, Matthiesen S (2015) ChemPhysChem 16(13):2760–2767

    Article  CAS  Google Scholar 

  43. Bader RFW (2007) The lagrangian approach to chemistry. In: Matta CF, Boyd RJ (eds) The quantum theory of atoms in molecules. Wiley, Hoboken, pp 35–59

    Chapter  Google Scholar 

  44. Bader RFW (1985) Acc Chem Res 18(1):9–15

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to sincerely thank Michael Dreist, who initiated the ideas behind this paper before he unexpectedly passed away in December 2018. This paper is dedicated to his memory. Further we would like to thank our colleagues at Bayer, namely Erzsébet “Bözsi” Pogány, Katja Timm, and finally Frank Neese and Walter Thiel (*1949–†2019) from Max-Planck-Institut für Kohlenforschung in Mülheim an der Ruhr for their great support.

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Division Crop Science, Bayer AG, Alfred-Nobel-Str. 50, 40789, Monheim am Rhein, Germany

    Michael Edmund Beck

  2. FAccTs GmbH, Rolandstr. 67, 50677, Cologne, Germany

    Christoph Riplinger

  3. Division Crop Science, Computational Life Science, Small Molecules, Bayer SAS, 14, impasse Pierre Baizet CS 99163, 69263, Lyon, France

    Jacopo Negroni

  4. Division Crop Science, Small-Molecules-Research/Computational Life Science, Bayer AG, Alfred-Nobel-Str. 50, 40789, Monheim am Rhein, Germany

    Svend Matthiesen & Michael Kohnen

Authors
  1. Michael Edmund Beck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jacopo Negroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Svend Matthiesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Kohnen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christoph Riplinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MEB provided conceptualization of the study, supervision, as well as project administration, funding acquisition and provision of computing resources. MEB also contributed to investigation and analysis, as well as methodology (QTAIM). JN: provision and creation of protein model. CR: Project administration, Data curation, Formal analysis, Investigation, Methodology, Validation, Software. SM and MK performed calculations and set up the required computing infrastructure. MEB, CR, and JN equally involved themselves in drafting, reviewing and editing of the manuscript.

Corresponding authors

Correspondence to Michael Edmund Beck or Christoph Riplinger.

Ethics declarations

Conflict of interest

MEB, JN, SM, and MK are employees of Bayer AG, which is marketing products containing prothioconazole as active ingredient; CR is founder of FAccTs GmbH, which is marketing the ORCA software suite, for commercial usage. For academic use, ORCA remains free.

Additional information

In Memoriam Michael Dreist.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 556 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Beck, M.E., Negroni, J., Matthiesen, S. et al. A binding mode hypothesis for prothioconazole binding to CYP51 derived from first principles quantum chemistry. J Comput Aided Mol Des 35, 493–503 (2021). https://doi.org/10.1007/s10822-020-00331-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-020-00331-z

Keywords

Search

Navigation