Analysing Multitarget Activity Landscapes using Protein-Ligand Interaction Fingerprints: Interaction cliffs
Kooistra, Albert J.
de Graaf, Chris
Medina-Franco, José L.
Journal of Chemical Information and Modeling
Journal of Chemical Information and Modeling 2015, 55 (2), pp 251–262 DOI: 10.1021/ci500721x
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Méndez-Lucio, O., Kooistra, A. J., de Graaf, C., Bender, A., & Medina-Franco, J. L. (2015). Analysing Multitarget Activity Landscapes using Protein-Ligand Interaction Fingerprints: Interaction cliffs. Journal of Chemical Information and Modeling, 55 (2), 251-262. https://doi.org/10.1021/ci500721x
This is the original submitted version, before peer review. The final peer-reviewed version is available from ACS at http://pubs.acs.org/doi/abs/10.1021/ci500721x.
Activity landscape modelling is mostly a descriptive technique that allows rationalizing continuous and discontinuous SARs, however the interpretation, especially of activity cliffs, is not straightforward. As the nature of activity cliffs depends on the ligand and the target, information regarding both should be included in the analysis. A specific way to include this information is using protein-ligand interaction fingerprints (IFPs). In this paper we report the activity landscape modelling of 507 ligand-kinase complexes (from KLIFS database) adding IFP, which facilitates the analysis and interpretation of activity cliffs. To this end, we introduce the structure-activity-interaction similarity (SAIS) maps that incorporate information of ligand-target contact similarity. We also introduce the concept of interaction cliffs defined as ligand-target complexes with high structural and interaction similarity, but a large potency difference of the ligands. Moreover, the specific interaction information allowed the identification of activity cliff hot spots, which help to rationalize activity cliffs from the target point of view. In general, the information provided by IFPs helps to get a better understanding when modelling an activity landscape. This paper shows examples of analyses that can be carried out when IFPs are added to the activity landscape model.
Activity landscape, Activity cliffs, Interaction cliffs, Protein-ligand interaction fingerprints, Kinase inhibitors, SAS maps
M-L is very grateful to CONACyT (No. 217442/312933) and the Cambridge Overseas Trust for funding. AB thanks Unilever for funding and the European Research Council for a Starting Grant (ERC-2013-StG- 336159 MIXTURE). This work was supported by a scholarship from the Secretariat of Public Education and the Mexican government.
External DOI: https://doi.org/10.1021/ci500721x
This record's URL: http://www.repository.cam.ac.uk/handle/1810/247367