Automated Structure-Activity Relationship Mining: Connecting Chemical Structure to Biological Profiles.
Understanding the structure-activity relationships (SARs) of small molecules is important for developing probes and novel therapeutic agents in chemical biology and drug discovery. Increasingly, multiplexed small-molecule profiling assays allow simultaneous measurement of many biological response parameters for the same compound (e.g., expression levels for many genes or binding constants against many proteins). Although such methods promise to capture SARs with high granularity, few computational methods are available to support SAR analyses of high-dimensional compound activity profiles. Many of these methods are not generally applicable or reduce the activity space to scalar summary statistics before establishing SARs. In this article, we present a versatile computational method that automatically extracts interpretable SAR rules from high-dimensional profiling data. The rules connect chemical structural features of compounds to patterns in their biological activity profiles. We applied our method to data from novel cell-based gene-expression and imaging assays collected on more than 30,000 small molecules. Based on the rules identified for this data set, we prioritized groups of compounds for further study, including a novel set of putative histone deacetylase inhibitors.
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, USA.
Mathias J
MJ
Wawer
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, USA.
David E
DE
Jaramillo
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, USA Mathematical Institute of the Slovak Academy of Sciences, Košice, Slovakia (on leave).
Vlado
V
Dančík
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, USA Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Departments of Neurology and Psychiatry, Harvard Medical School, Boston, MA, USA.
Daniel M
DM
Fass
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, USA Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Departments of Neurology and Psychiatry, Harvard Medical School, Boston, MA, USA.
Stephen J
SJ
Haggarty
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, USA.
Alykhan F
AF
Shamji
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, USA.
Bridget K
BK
Wagner
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, USA.
Stuart L
SL
Schreiber
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, USA pclemons@broadinstitute.org.
Paul A
PA
Clemons
D001331:Automation; D002626:Chemistry, Pharmaceutical / Q000379:methods; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods*; D057225:Data Mining / Q000379:methods; D055808:Drug Discovery; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry; D006801:Humans; D012984:Software; D013329:Structure-Activity Relationship
D056572:Histone Deacetylase Inhibitors
association-rule mining; frequent-itemset mining; high-content screening; small-molecule profiling; structure–activity relationships