How polypharmacologic is each chemogenomics library?

Future Drug Discovery
Eric NiTimothy Cardozo

Abstract

High-throughput phenotypic screens have emerged as a promising avenue for small-molecule drug discovery. The challenge faced in high-throughput phenotypic screens is target deconvolution once a small molecule hit is identified. Chemogenomics libraries have emerged as an important tool for meeting this challenge. Here, we investigate their target-specificity by deriving a 'polypharmacology index' for broad chemogenomics screening libraries. All known targets of all the compounds in each library were plotted as a histogram and fitted to a Boltzmann distribution, whose linearized slope is indicative of the overall polypharmacology of the library. Comparison of libraries clearly distinguished the most target-specific library, which might be assumed to be more useful for target deconvolution in a phenotypic screen.

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Citations

Jul 25, 2020·Cell Chemical Biology·Stephen M CanhamJeremy L Jenkins

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Software Mentioned

tHTS
Simplified
ICM script
MATLAB Curve Fitting Suite
pHTS
RDkit
ChEMBL
MIPE Mechanism Interrogation PlatE
Molsoft
Molecular Input Line Entry System ( SMILES )

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