Structural Interpretation of Activity Cliffs Revealed by Systematic Analysis of Structure−Activity Relationships in Analog Series
| Autor: | Jürgen Bajorath, Mihiret T. Sisay, Lisa Peltason |
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| Rok vydání: | 2009 |
| Předmět: |
Models
Molecular Quantitative structure–activity relationship General Chemical Engineering Molecular Conformation Library and Information Sciences Interpretation (model theory) Structure-Activity Relationship Drug Discovery Combinatorial Chemistry Techniques Enzyme Inhibitors skin and connective tissue diseases Mathematics Basis (linear algebra) Series (mathematics) business.industry fungi Substitution (logic) Thrombin General Chemistry Receptor TIE-2 Computer Science Applications body regions Discontinuity (linguistics) Order (biology) Complementarity (molecular biology) Factor Xa Artificial intelligence business Biological system Factor Xa Inhibitors |
| Zdroj: | Journal of Chemical Information and Modeling. 49:2179-2189 |
| ISSN: | 1549-960X 1549-9596 |
| Popis: | Discontinuity in structure-activity relationships (SARs) is caused by so-called activity cliffs and represents one of the major caveats in SAR modeling and lead optimization. At activity cliffs, small structural modifications of compounds lead to substantial differences in potency that are essentially unpredictable using quantitative structure-activity relationship (QSAR) methods. In order to better understand SAR discontinuity at the molecular level of detail, we have analyzed different compound series in combinatorial analog graphs and determined substitution patterns that introduce activity cliffs of varying magnitude. So identified SAR determinants were then analyzed on the basis of complex crystal structures to enable a structural interpretation of SAR discontinuity and underlying activity cliffs. In some instances, SAR discontinuity detected within analog series could be well rationalized on the basis of structural data, whereas in others a structural explanation was not possible. This reflects the intrinsic complexity of small molecule SARs and suggests that the analysis of short-range receptor-ligand interactions seen in X-ray structures is insufficient to comprehensively account for SAR discontinuity. However, in other cases, SAR information extracted from ligands was incomplete but could be deduced taking X-ray data into account. Thus, taken together, these findings illustrate the complementarity of ligand-based SAR analysis and structural information. |
| Databáze: | OpenAIRE |
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