SAR Index: Quantifying the Nature of Structure−Activity Relationships
Abstract
Structure-activity relationships (SARs) can display very different features. Small chemical modifications of active molecules often dramatically alter biological responses. By contrast, structurally diverse molecules can have similar activity. SARs can also be heterogeneous in nature. For example, for structurally diverse molecules with similar activity, closely related analogs might have significant differences in potency. Given the inherent complexity of SARs, it has been very difficult to estimate SAR characteristics from molecular structure. On the basis of systematic correlation of 2D structural similarity and compound potency, we have developed a function termed "SAR Index" that quantitatively describes the nature of SARs and establishes different SAR categories: continuous, discontinuous, heterogeneous-relaxed, and heterogeneous-constrained. These heterogeneous SAR categories are described for the first time. Given a set of active compounds and their potency values, SAR Index calculations can estimate how likely it is to identify structurally distinct molecules having similar activity.
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SAR discontinuities occur when small structural modifications lead to very large biological potency changes, not consistent with the similarity-property principle and falling outside the applicability domain of linear QSAR models.
“In contrast, SAR discontinuities21 occur when small structural modifications lead to very large biological potency changes, not consistent with the SPP and falling outside the applicability domain of linear QSAR models.”
From QSAR without borders (2020) · cites this paper as [21]
In QSAR modeling the presence of SAR continuities and discontinuities in sets of active compounds is not mutually exclusive; continuous and discontinuous SARs coexist in many data sets.
“In QSAR modeling the presence of SAR continuities and discontinuities in sets of active compounds is not mutually exclusive. Rather, continuous and discontinuous SARs coexist in many data sets21 resulting in the presence of adjacent gently sloped and rugged regions in activity landscapes (Figure 2).”
From QSAR without borders (2020) · cites this paper as [21]
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Self-citationOn Outliers and Activity CliffsWhy QSAR Often Disappoints
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Molecular similarity analysis in virtual screening: foundations, limitations and novel approaches
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Self-citationSearching Techniques for Databases of Two- and Three-Dimensional Chemical Structures
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Muratov, E. N., Bajorath, J., Sheridan, R. P., Tetko, I. V., Filimonov, D., Poroikov, V., Oprea, T. I., Baskin, I. I., Varnek, A., Roitberg, A., et al. (2020) · Chemical Society Reviews · doi:10.1039/d0cs00098a · Cited by 913 · see citing works
Self-citationSystematic analysis of genome-wide fitness data in yeast reveals novel gene function and drug action
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“This finding can be attributed to structurally diverse compounds that inhibit different proteins within the same pathway, or to different compound structures that inhibit the same target [ 45 ,46].”
BackgroundPeltason, L., Iyer, P., & Bajorath, J. (2010) · Journal of Chemical Information and Modeling · doi:10.1021/ci100091e · Cited by 85 · see citing works
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- Authors
- Peltason, L., & Bajorath, J.
- Affiliations
- University of Bonn (DE)
- Corresponding author
- Bajorath, Jürgen
- ORCID
- Bajorath, Jürgen
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2007-09-29
- Volume
- 50
- Issue
- 23
- Pages
- 5571-5578
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2034541070
- Cited by
- 201
- References
- 6
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 7 · 2023: 4 · 2022: 10 · 2021: 6 · 2020: 8 · 2019: 3 · 2018: 8 · 2017: 6 · 2016: 5 · 2015: 7 · 2014: 11 · 2013: 16 · 2012: 18
- FWCI
- 19.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
- Physical Sciences › Mathematics › Geometry and Topology › Graph theory and applications
- Keywords
- structure-activity relationship
- MeSH terms
- Adenosine Deaminase, Carbonic Anhydrases, Data Interpretation, Statistical, Enzyme Inhibitors, Ribonuclease, Pancreatic, Thromboxane-A Synthase, Thymidylate Synthase, Factor Xa, Quantitative Structure-Activity Relationship, Adenosine Deaminase Inhibitors
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