Knowing the cellular targets of a small molecule can help researchers better understand the biological basis of a disease and develop new drugs to treat that disease. Whether it is an FDA-approved drug with an unknown mechanism of action, a natural product, or a novel small molecule identified from a laboratory screen, researchers must understand how a molecule of interest exerts its effects. These insights can pave the way for development of a compound as a molecular probe or possibly a new drug with well-characterized on- and off-target effects.
A team of researchers at the Broad can help realize this goal. With deep expertise in key scientific areas, the Mechanism of Action team brings state-of-the-art tools and a highly integrated approach to bear on small molecules with unknown cellular targets. Their approach combines the strengths of four complementary strategies: proteomics, RNAi screening, expression profiling, and computational analysis.
Proteomics: Broad researchers use mass spectrometry to identify the protein targets that bind to a small molecule.
RNAi screening: Genetic perturbations offer researchers insights into the individual genes and pathways involved in a small molecule’s effects.
Expression profiling: By looking at the expression of thousands of genes after treatment with a small molecule, researchers can glean a small molecule’s gene-expression signature, which can in turn be compared to an extensive library of signatures from other small molecules (The Connectivity Map)
to draw connections to compounds with known mechanisms of action.
Computational analysis: The Broad Mechanism of Action team brings together all of the data generated through these approaches using computational analyses. The team can further inform these analyses using the rich set of historical Broad Institute screening data (including, e.g., from ChemBank).
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