Skip to main content
SpringerLink
Log in

Molecular shape and electrostatics in the encoding of relevant chemical information

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

Summary

We propose a molecule’s chemistry can be hidden by representations of its shape and electrostatic field while retaining crucial, pharmaceutically relevant, information. Necessary, but not sufficient, to this proposition are the importance of shape and electrostatics to activity, the facility to easily represent, store and compare field properties, and knowledge of the density of possible drug-like molecules within a given radius of physical similarity. We provide methods and evidence to support the conclusion that a useful encoding is practical and propose tests for falsification.

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

Similar content being viewed by others

References

  1. Hohenberg P., Kohn W., (1964) Phys. Rev. B, 136:864

    Article  Google Scholar 

  2. Bissantz C., Folkers G., Rognan D., (2000) J. Med. Chem. 43: 4759

    Article  CAS  Google Scholar 

  3. Nicholls A., MacCuish N.E., MacCuish J.D., (2004) JCAMD, 18: 451

    CAS  Google Scholar 

  4. Rush T.S., Grant J.A., Mosyak L., Nicholls A., (2005) J. Med. Chem. 48(5): 1489

    Article  CAS  Google Scholar 

  5. Katz, A.H., Tawa, G.J., Mason, K., Gove, S. and Alvarez, J.C., Comput. Chem., 92 (2004), ACS, Anaheim

  6. Tawa, G.J., Katz, A.H. and Alvarez, J.C., Comput. Chem., 244 (2004) ACS, Philadelphia

  7. Petit-Zeman, S., 4th Horizon Symposium, Oct. 23–25, 2003

  8. Bohacek R.S., McMartin C., Guida W.C., (1996) Med. Res. Rev. 16: 3

    Article  CAS  Google Scholar 

  9. Masek B.B, Merchant A., Matthews J.B., (1993) Proteins 17: 193

    Article  CAS  Google Scholar 

  10. Grant J.A., Pickup B.T., (1995) J. Phys. Chem. 99: 3503

    Article  CAS  Google Scholar 

  11. Grant J.A., Pickup B.T., (1996) J. Comput. Chem, 17: 1653

    Article  CAS  Google Scholar 

  12. Grant, J.A., Haigh, J.A., Nicholls, A. and Pickup, B.T., JCICS, Vol. 20, (2005) (In press)

  13. Nicholls, A., Daylight Users Group Meeting, Feb. 24–27th, 1998

  14. Hall, D.W. and Spencer, G.L., Elementary Topology, Wiley, 1955, p. 59ff

  15. Fink T., Bruggesser H., Reymond J.-L, 2005 Angew. Chem. Int. Ed. 44: 1504

    Article  CAS  Google Scholar 

  16. Putta S., Christian L., Beroza P., Greene J., 2002 JCICS 42: 1230

    CAS  Google Scholar 

  17. Kearsley S.K., Smith G.M., (1990) Tet. Comp. Met 3: 615

    Article  CAS  Google Scholar 

  18. Good A.C., Hodgkin E.E., Richards W.G., (1992) JCICS. 32: 188

    CAS  Google Scholar 

  19. Good A.C., Richards W.G., (1993) J. Chem. Inf. Comput. Sci., 33: 112

    CAS  Google Scholar 

  20. Lin, J.-H. and Clark, T., J. Chem. Inf. Model (2005) 45 (in␣press)

  21. Kazhdan, M.M., Thesis Dissertation, Comp. Sci. Dept., Princeton, June 2004

  22. Duncan B.S., Olson A.J, 1993 Biopolymers 33: 219

    Article  CAS  Google Scholar 

  23. Leicester S.E., Finney J.L., Bywater R.P, 1988 J. Mol. Graphics 6: 104

    Article  CAS  Google Scholar 

  24. Max N.L., Getzoff E.D., 1988 IEEE Comput. Graphics Appl. 8: 42

    Article  Google Scholar 

  25. Ritchie, D.W. and Kemp, G.J., Proteins: Structure, Function & Genetics, John Wiley & Sons, 1999

  26. Ritchie D.W., Kemp G.J.L., 1999 J. Comput. Chem. 20(4): 383

    Article  CAS  Google Scholar 

  27. Grant, J.A. and Pickup, B.T., In W. Gunsteren and P.K. Weiner (Eds.), Computer Simulation of Biomolecular Systems, Vol. 3, Kluwer, 1997

  28. Perola E., Charifson P., (2004) J. Med. Chem. 47:2499

    Article  CAS  Google Scholar 

  29. Boström J., Norby P.-O., Liljefors T., (1998) JCAMD 12:383

    Google Scholar 

  30. ROCS 2.0, Omega 1.1, WABE 0.9, EON 1.0, OpenEye Scientific Software, Santa Fe, NM (www.eyesopen.com)

  31. Bostrom J., Greenwood J.R., Gottfries J., (2003) J. Mol. Graph Model 5:449

    Article  Google Scholar 

  32. Gasteiger, J. and Marsili, M., Tetrahedron Lett. (1978) 3181

  33. Durant J.L., Leland B.A., Henry D.R., Nourse J.G., (2002) J. Chem. Inf. Comput. Sci., 42: 1273

    Article  CAS  Google Scholar 

  34. Fingerprint, M., Mesa Analytics & Computing, LLC, Santa Fe, NM, www.mesaac.com

  35. Lu H., Chang D.J., Baratte B., Meijer L., Schulze-Gahmen U., (2005) J. Med. Chem. 48: 737

    Article  CAS  Google Scholar 

  36. MDDR (MDL Drug Data Report), MDL, Inc and Prous Science (1995–2005)

  37. Corina, Molecular Networks, GmbH Computerchemie Langemarckplatz 1, Erlangen, Germany

  38. Jones, H. Thesis Dissertation, Chemistry Dept., University of Sheffield, 2004

  39. Smith D.J., Forrest S., Hightower R.R., Perelson A.S., (1997) J. Theor. Biol. 189: 141

    Article  CAS  Google Scholar 

  40. Lapedes, A. and Farber R., Santa Fe Institute working paper 00-01-006

  41. Abagyan, R., Raush, E. and Budagyan, L. Safe Exchange of Chemical Information Symposium, March 14th 2005, San Diego, ACS

  42. vonNeumann, J. and Morgenstern, O., Theory of Games and Economic Behavior, Princeton Univ. Press, 1944

  43. Schneier, B., Applied Cryptography, Wiley, 1995

Download references

Acknowledgements

The authors wish to thank Mike Tennant and Andrew Jennings of Syrrx, Inc. (Takeda Pharmaceuticals) for help in constructing the MACE database and running large-scale ROCS calculations, Geoff Skillman for the curation of the MACE dataset, Robert Tolbert for help with WABE, James Haigh for construction of shape fingerprints on the Fesitin dataset and Mesa Analytics for the use of their fingerprinting code.

Author information

Authors and Affiliations

  1. OpenEye Scientific Software, Inc., 3600 Cerrillos Rd. Suite 1107, Santa Fe, NM, 87507, USA

    Anthony Nicholls

  2. AstraZeneca Pharmaceuticals, SK 10 4TF, Mereside, Macclesfield, Cheshire, England

    J. Andrew Grant

Authors
  1. Anthony Nicholls
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Andrew Grant
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anthony Nicholls.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nicholls, A., Grant, J. Molecular shape and electrostatics in the encoding of relevant chemical information. J Comput Aided Mol Des 19, 661–686 (2005). https://doi.org/10.1007/s10822-005-9019-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-005-9019-x

Keywords

Search

Navigation