Journal of Computer-Aided Molecular Design

, Volume 26, Issue 7, pp 805–819 | Cite as

R-group template CoMFA combines benefits of “ad hoc” and topomer alignments using 3D-QSAR for lead optimization

Article

Abstract

Template CoMFA methodologies extend topomer CoMFA by allowing user-designated templates, for example the experimental receptor-bound conformation of a prototypical ligand, to help determine the alignment of training and test set structures for 3D-QSAR. The algorithms that generate its new structural modality, template-constrained topomers, are described. Template CoMFA’s resolution of certain topomer CoMFA concerns, by providing user control of topological consistency and structural acceptability, is demonstrated for sixteen 3D-QSAR training sets, in particular the Selwood dataset.

Keywords

3D-QSAR Topomers Selwood Template CoMFA Ligand alignment 

Supplementary material

10822_2012_9583_MOESM1_ESM.sdf (83 kb)
All templates and training sets referenced in the Results section (SDF 82 kb)
10822_2012_9583_MOESM2_ESM.sdf (8 kb)
Supplementary material 2 (SDF 7 kb)
10822_2012_9583_MOESM3_ESM.sdf (6 kb)
Supplementary material 3 (SDF 6 kb)
10822_2012_9583_MOESM4_ESM.sdf (6 kb)
Supplementary material 4 (SDF 6 kb)
10822_2012_9583_MOESM5_ESM.sdf (45 kb)
Supplementary material 5 (SDF 45 kb)
10822_2012_9583_MOESM6_ESM.sdf (45 kb)
Supplementary material 6 (SDF 45 kb)
10822_2012_9583_MOESM7_ESM.sdf (145 kb)
Supplementary material 7 (SDF 144 kb)
10822_2012_9583_MOESM8_ESM.sdf (153 kb)
Supplementary material 8 (SDF 153 kb)
10822_2012_9583_MOESM9_ESM.sdf (254 kb)
Supplementary material 9 (SDF 254 kb)
10822_2012_9583_MOESM10_ESM.sdf (254 kb)
Supplementary material 10 (SDF 254 kb)
10822_2012_9583_MOESM11_ESM.sdf (254 kb)
Supplementary material 11 (SDF 254 kb)
10822_2012_9583_MOESM12_ESM.sdf (154 kb)
Supplementary material 12 (SDF 154 kb)
10822_2012_9583_MOESM13_ESM.sdf (158 kb)
Supplementary material 13 (SDF 157 kb)
10822_2012_9583_MOESM14_ESM.sdf (216 kb)
Supplementary material 14 (SDF 216 kb)
10822_2012_9583_MOESM15_ESM.sdf (110 kb)
Supplementary material 15 (SDF 110 kb)
10822_2012_9583_MOESM16_ESM.sdf (176 kb)
Supplementary material 16 (SDF 176 kb)
10822_2012_9583_MOESM17_ESM.sdf (68 kb)
Supplementary material 17 (SDF 67 kb)
10822_2012_9583_MOESM18_ESM.sdf (74 kb)
Supplementary material 18 (SDF 74 kb)
10822_2012_9583_MOESM19_ESM.sdf (191 kb)
Supplementary material 19 (SDF 190 kb)
10822_2012_9583_MOESM20_ESM.sdf (54 kb)
Supplementary material 20 (SDF 54 kb)

References

  1. 1.
    Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindberg SR, Schacht AL (2010) Nat Rev Drug Disc 9:203–214Google Scholar
  2. 2.
    Cramer RD, Cruz P, Stahl G, Curtiss WC, Campbell B, Masek BB, Soltanshahi F (2008) J Chem Inf Model 48:2180–2195CrossRefGoogle Scholar
  3. 3.
    Doweyko A (2007) J Comp Aided Drug Des 18:587–596CrossRefGoogle Scholar
  4. 4.
    Stouch TR (2012) J Comp Aided Drug Des 26:125–134CrossRefGoogle Scholar
  5. 5.
    Cramer RD, Clark RD, Patterson DE, Ferguson AM (1996) J Med Chem 39:3060–3069CrossRefGoogle Scholar
  6. 6.
    Jilek RJ, Cramer RD (2004) J Chem Inf Comp Sci 44:1221–1227CrossRefGoogle Scholar
  7. 7.
    Cramer RD, Jilek RJ, Guessregen S, Clark SJ, Wendt B, Clark RD (2004) J Med Chem 47(6777):6791Google Scholar
  8. 8.
    Cramer RD (2003) J Med Chem 46:374–389CrossRefGoogle Scholar
  9. 9.
    Cramer RD (2012) J Comp Aided Drug Des 25:197–201CrossRefGoogle Scholar
  10. 10.
    Selwood DL, Livingston DJ, Comley JCW, O’Dowd AB, Hudson AT, Jackson P, Jandu KS, Rose VS, Stables JM (1990) J Med Chem 33:136–142CrossRefGoogle Scholar
  11. 11.
    Nicoletti O, Gillet VJ, Fleming PJ, Green DVS (2002) J Med Chem 45:5069–5080CrossRefGoogle Scholar
  12. 12.
    Kubinyi H (1994) Quant Struct Act Relat 13:285–294Google Scholar
  13. 13.
    So S-S, Karplus M (1996) J Med Chem 39:1521–1540CrossRefGoogle Scholar
  14. 14.
    Wendt B, Cramer RD (2008) J Comp Aided Drug Des 22:541–551CrossRefGoogle Scholar
  15. 15.
    Jain AN (2004) J Med Chem 47:941–961Google Scholar
  16. 16.
    Maggiora GM (2006) J Chem Inf Model 46:1535CrossRefGoogle Scholar
  17. 17.
    Taleb NN (2007) The Black Swan: the impact of the highly Improbable, Random House, ISBN 978-1-4000-6351-2Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  1. 1.Tripos DESt. LouisUSA

Personalised recommendations