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Poster at 6th Joint Sheffield Conference on Chemoinformatics
by Nina Jeliazkova, Nikolay T. Kochev, Vedrin Jeliazkov
The Structure-Activity Relationships (SAR) landscape and activity cliffs concepts are a popular analysis and visualisation technique, with origins in medicinal chemistry and receptor-ligand interactions modelling. While intuitive, the definition of an activity cliff as a “pair of structurally similar compounds with large differences in potency” is commonly recognized as ambiguous. We have recently proposed a new and efficient method for identifying activity cliffs and visualization of activity landscapes . The method introduces a probabilistic measure - the likelihood of a compound having large activity difference compared to other compounds, while being highly similar to them. The likelihood is effectively a quantification of a SAS Map with defined thresholds and does not require the storage of the pairwise similarity matrix. The method generates a list of individual compounds, ranked according to their likelihood of being involved in the formation of activity cliffs , and goes beyond characterizing cliffs by structure pairs only. Every compound is associated with zero, one, or more compounds with similarity and activity difference above the defined threshold. The paired structures can be easily retrieved by a standard similarity query. The arrangement as a graph naturally emerges from the set of top ranked compounds, as they are usually interconnected as activity cliffs pairs. The popular matched molecular pairs approach could be considered a special case, but is also improved by being able to identify multiple matching pairs at once. We now extend the landscape analysis and visualisation of datasets, where the chemical structures are represented by more than one tautomer, and study the influence of the tautomerization on the SAR landscape. The tautomer generation relies on the Ambit-Tautomer open source package, developed by the authors . Finally, the method is implemented as part of an existing open source Ambit package  and could be accessed via an OpenTox API compliant web service. OpenTox API provides a uniform REST web service application programming interface (API) to chemical structures, experimental data and calculated properties, descriptor calculation, model building, validation and reporting . The AMBIT web services package  is being developed by Ideaconsult Ltd. and is one of the several existing independent implementations of the OpenTox API, providing data sharing and remote calculations capabilities. Visualisation of the ranked activity cliffs by bubble charts is presented and interactive visualisation at http://toxmatch.sf.net are available.