Using Multiple Microenvironments to Find Similar Ligand-Binding Sites: Application to Kinase Inhibitor Binding
The recognition of cryptic small-molecular binding sites in protein structures is important for understanding off-target side effects and for recognizing potential new indications for existing drugs. Current methods focus on the geometry and detailed chemical interactions within putative binding poc...
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| Format: | Online |
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Public Library of Science
2011
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248393/ |
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pubmed-3248393 |
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pubmed-32483932012-01-04 Using Multiple Microenvironments to Find Similar Ligand-Binding Sites: Application to Kinase Inhibitor Binding Liu, Tianyun Altman, Russ B. Research Article The recognition of cryptic small-molecular binding sites in protein structures is important for understanding off-target side effects and for recognizing potential new indications for existing drugs. Current methods focus on the geometry and detailed chemical interactions within putative binding pockets, but may not recognize distant similarities where dynamics or modified interactions allow one ligand to bind apparently divergent binding pockets. In this paper, we introduce an algorithm that seeks similar microenvironments within two binding sites, and assesses overall binding site similarity by the presence of multiple shared microenvironments. The method has relatively weak geometric requirements (to allow for conformational change or dynamics in both the ligand and the pocket) and uses multiple biophysical and biochemical measures to characterize the microenvironments (to allow for diverse modes of ligand binding). We term the algorithm PocketFEATURE, since it focuses on pockets using the FEATURE system for characterizing microenvironments. We validate PocketFEATURE first by showing that it can better discriminate sites that bind similar ligands from those that do not, and by showing that we can recognize FAD-binding sites on a proteome scale with Area Under the Curve (AUC) of 92%. We then apply PocketFEATURE to evolutionarily distant kinases, for which the method recognizes several proven distant relationships, and predicts unexpected shared ligand binding. Using experimental data from ChEMBL and Ambit, we show that at high significance level, 40 kinase pairs are predicted to share ligands. Some of these pairs offer new opportunities for inhibiting two proteins in a single pathway. Public Library of Science 2011-12-29 /pmc/articles/PMC3248393/ /pubmed/22219723 http://dx.doi.org/10.1371/journal.pcbi.1002326 Text en Liu, Altman. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Liu, Tianyun Altman, Russ B. |
| spellingShingle |
Liu, Tianyun Altman, Russ B. Using Multiple Microenvironments to Find Similar Ligand-Binding Sites: Application to Kinase Inhibitor Binding |
| author_facet |
Liu, Tianyun Altman, Russ B. |
| author_sort |
Liu, Tianyun |
| title |
Using Multiple Microenvironments to Find Similar Ligand-Binding Sites: Application to Kinase Inhibitor Binding |
| title_short |
Using Multiple Microenvironments to Find Similar Ligand-Binding Sites: Application to Kinase Inhibitor Binding |
| title_full |
Using Multiple Microenvironments to Find Similar Ligand-Binding Sites: Application to Kinase Inhibitor Binding |
| title_fullStr |
Using Multiple Microenvironments to Find Similar Ligand-Binding Sites: Application to Kinase Inhibitor Binding |
| title_full_unstemmed |
Using Multiple Microenvironments to Find Similar Ligand-Binding Sites: Application to Kinase Inhibitor Binding |
| title_sort |
using multiple microenvironments to find similar ligand-binding sites: application to kinase inhibitor binding |
| description |
The recognition of cryptic small-molecular binding sites in protein structures is important for understanding off-target side effects and for recognizing potential new indications for existing drugs. Current methods focus on the geometry and detailed chemical interactions within putative binding pockets, but may not recognize distant similarities where dynamics or modified interactions allow one ligand to bind apparently divergent binding pockets. In this paper, we introduce an algorithm that seeks similar microenvironments within two binding sites, and assesses overall binding site similarity by the presence of multiple shared microenvironments. The method has relatively weak geometric requirements (to allow for conformational change or dynamics in both the ligand and the pocket) and uses multiple biophysical and biochemical measures to characterize the microenvironments (to allow for diverse modes of ligand binding). We term the algorithm PocketFEATURE, since it focuses on pockets using the FEATURE system for characterizing microenvironments. We validate PocketFEATURE first by showing that it can better discriminate sites that bind similar ligands from those that do not, and by showing that we can recognize FAD-binding sites on a proteome scale with Area Under the Curve (AUC) of 92%. We then apply PocketFEATURE to evolutionarily distant kinases, for which the method recognizes several proven distant relationships, and predicts unexpected shared ligand binding. Using experimental data from ChEMBL and Ambit, we show that at high significance level, 40 kinase pairs are predicted to share ligands. Some of these pairs offer new opportunities for inhibiting two proteins in a single pathway. |
| publisher |
Public Library of Science |
| publishDate |
2011 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248393/ |
| _version_ |
1611497355124670464 |