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Mechanism-of-action analysis of structurally and biologically similar compounds

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2nd year PhD Talk

The BioMAP systems are high-quality phenotypic screening assays and part of EPA ’s ToxCast effort to prioritise chemical testing. Based on a robust metric, the nScore, 370 compounds were grouped into 82 clusters using their BioMAP profiles. It was found that compounds having a structural similarity corresponding to a Tanimoto coefficient of > 0.7 had similar BioMAP profiles. Since 4 out of the 82 clusters had compounds that were similar biologically and structurally, we hypothesized that these compounds had a similar mechanism of action. We decided to investigate the putative molecular targets of these using a novel target prediction algorithm, and for 3 out of the 4 clusters, all compounds had the same target profile, while no targets were predicted for the remaining cluster. Another 466 compounds that were not initially clustered were used to validate the above hypothesis. Using target prediction alone, these compounds were associated to one of the 3 clusters if they matched the common target profile of the cluster. Compound associated this way were not only structurally similar, but also had a BioMAP profile that closely matched the BioMAP profiles of the other compounds in the cluster. Consequently, compounds with similar mechanisms of action may be a result of chemical similarity and may yield similar biological activity.

This talk is part of the Theoretical Chemistry Informal Seminars series.

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