Abstract
In this chapter we discuss the landscape view of structure–activity relationships (SARs). The motivation for such a view is that SARs come in a variety of forms, such as those where small changes in structure lead to small changes in activity or where small structural lead to significant changes in activity (also termed activity cliffs). Thus, an SAR dataset is viewed as a landscape comprised of smooth plains, rolling hills, and jagged gorges. We review the history of this view and early quantitative approaches that attempted to encode the landscape. We then discuss some recent developments that directly characterize structure–activity landscapes, in one case with the goal of highlighting activity cliffs while the other allows one to resolve different types of SAR that may be present in a dataset. We highlight some applications of these approaches, such as predictive model development and SAR elucidation, to SAR datasets obtained from the literature. Finally, we conclude with a summary of the landscape approach and why it provides an intuitive and rigorous alternative to standard views of structure–activity data.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Patterson, D. E.; Cramer, R. D.; Ferguson, A. M.; Clark, R. D.; Weinberger, L. E., Neighborhood Behavior: A Useful Concept for Validation of “Molecular Diversity” Descriptors. J. Med. Chem. 1996, 39, 3049–3059.
Leach, A. G.; Jones, H. D.; Cosgrove, D. A.; Kenny, P. W.; Ruston, L.; MacFaul, P.; Wood, J. M.; Colclough, N.; Law, B., Matched Molecular Pairs as a Guide in the Optimization of Pharmaceutical Properties; a Study of Aqueous Solubility, Plasma Protein Binding and Oral Exposure. J. Med. Chem. 2006, 49, 6672–6682.
Sheridan, R. P.; Hunt, P.; Culberson, J. C., Molecular Transformations as a Way of Finding and Exploiting Consistent Local QSAR. J. Chem. Inf. Model. 2006, 46 (1), 180–192.
Tran, J. A.; Chen, C. W.; Jiang, W.; Tucci, F. C.; Fleck, B. A.; Marinkovic, D.; Arellano, M.; Chen, C.; Tran, J. A.; Chen, C. W.; Jiang, W.; Tucci, F. C.; Fleck, B. A.; Marinkovic, D.; Arellano, M.; Chen, C., Pyrrolidines as Potent Functional Agonists of the Human Melanocortin-4 Receptor. Bioorg. Med. Chem. Lett. 2007, 17, 5165–5170.
Tran, J. A.; Tucci, F. C.; Jiang, W.; Marinkovic, D.; Chen, C. W.; Arellano, M.; Markison, S.; Fleck, B. A.; Wen, J.; White, N. S.; Pontillo, J.; Saunders, J.; Marks, D.; Hoare, S. R.; Madan, A.; Foster, A. C.; Chen, C.; Tran, J. A.; Tucci, F. C.; Jiang, W.; Marinkovic, D.; Chen, C. W.; Arellano, M.; Markison, S.; Fleck, B. A.; Wen, J.; White, N. S.; Pontillo, J.; Saunders, J.; Marks, D.; Hoare, S. R.; Madan, A.; Foster, A. C.; Chen, C., Pyrrolidinones as Orally Bioavailable Antagonists of the Human Melanocortin-4 Receptor with Anti-Cachectic Activity. Bioorg. Med. Chem. Lett. 2007, 15, 5166–5176.
Maggiora, G. M.; Maggiora, G. M., On Outliers and Activity Cliffs--Why QSAR Often Disappoints. J. Chem. Inf. Model. 2006, 46, 1535–1535.
Guha, R.; Van Drie, J. H., The Structure-Activity Landscape Index: Identifying and Quantifying Activity-Cliffs. J. Chem. Inf. Model. 2008, 48 (3), 646–658.
Bertz, S., The First General Index of Molecular Complexity. J. Am. Chem. Soc. 1981, 103 (12), 3599–3601.
Allu, T. K.; Oprea, T. I., Rapid Evaluation of Synthetic and Molecular Complexity for in Silico Chemistry. J. Chem. Inf. Model. 2005, 45 (5), 1237–1243.
Peltason, L.; Bajorath, J., SAR Index: Quantifying the Nature of Structure-Activity Relationships. J. Med. Chem. 2007, 50, 5571–5578.
Lehninger, A. L., Lehninger Principles of Biochemistry. 4th ed.; W.H. Freeman: New York, 2004.
Guha, R.; Van Drie, J. H., Assessing How Well a Modeling Protocol Captures a Structure-Activity Landscape. J. Chem. Inf. Model. 2008, 48 (8), 1716–1728.
Duch, W., Feature Extraction: Foundations and Applications. Springer: Berlin, 2006; Vol. 207.
Takahashi, H.; Bekkali, Y.; Capolino, A. J.; Gilmore, T.; Goldrick, S. E.; Kaplita, P. V.; Liu, L.; Nelson, R. M.; Terenzio, D.; Wang, J.; Zuvela-Jelaska, L.; Proudfoot, J.; Nabozny, G.; Thomson, D.; Takahashi, H.; Bekkali, Y.; Capolino, A. J.; Gilmore, T.; Goldrick, S. E.; Kaplita, P. V.; Liu, L.; Nelson, R. M.; Terenzio, D.; Wang, J.; Zuvela-Jelaska, L.; Proudfoot, J.; Nabozny, G.; Thomson, D., Discovery and SAR Study of Novel Dihydroquinoline Containing Glucocorticoid Receptor Agonists. Bioorg. Med. Chem. Lett. 2007, 17, 5091–5095.
Takahashi, H.; Bekkali, Y.; Capolino, A. J.; Gilmore, T.; Goldrick, S. E.; Nelson, R. M.; Terenzio, D.; Wang, J.; Zuvela-Jelaska, L.; Proudfoot, J.; Nabozny, G.; Thomson, D.; Takahashi, H.; Bekkali, Y.; Capolino, A. J.; Gilmore, T.; Goldrick, S. E.; Nelson, R. M.; Terenzio, D.; Wang, J.; Zuvela-Jelaska, L.; Proudfoot, J.; Nabozny, G.; Thomson, D., Discovery and SAR Study of Novel Dihydroquinoline Containing Glucocorticoid Receptor Ligands. Bioorg. Med. Chem. Lett. 2006, 16, 1549–1552.
Erdos, P.; Renyi, A., On Random Graphs. Publ Math. 1959, 6, 290–297.
Freeman, L. C., Centrality in Social Networks I: Conceptual Clarification. Social Networks 1979, 1, 215–239.
Wasserman, S.; Faust, K., Social Network Analysis: Methods and Applications. Cambridge: Cambridge University Press, 1994.
Wawer, M.; Peltason, L.; Weskamp, N.; Teckentrup, A.; Bajorath, J., Structure-Activity Relationship Anatomy by Network-like Similarity Graphs and Local Structure-Activity Relationship Indices. J. Med. Chem. 2008, 51 (19), 6075–6084.
Wawer, M.; Peltason, L.; Bajorath, J., Elucidation of Structure-Activity Relationship Pathways in Biological Screening Data. J. Chem. Inf. Model. 2009, 52 (4), 1075–1080.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Guha, R. (2010). The Ups and Downs of Structure–Activity Landscapes. In: Bajorath, J. (eds) Chemoinformatics and Computational Chemical Biology. Methods in Molecular Biology, vol 672. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-839-3_3
Download citation
DOI: https://doi.org/10.1007/978-1-60761-839-3_3
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-60761-838-6
Online ISBN: 978-1-60761-839-3
eBook Packages: Springer Protocols