How can I predict binding affinity without a target protein structure?
Why traditional ligand-based QSAR methods have fallen short You might be sceptical about ligand-based QSAR approaches; many researchers are. We discussed why there has…
Abstract
We have previously validated a probabilistic framework that combined computational approaches for predicting the biological activities of small molecule drugs. Molecule comparison methods included molecular structural similarity metrics and similarity computed from lexical analysis of text in drug package inserts.
Here we present an analysis of novel drug/target predictions, focusing on those that were not obvious based on known pharmacological crosstalk. Considering those cases where the predicted target was an enzyme with known 3D structure allowed incorporation of information from molecular docking and protein binding pocket similarity in addition to ligand-based comparisons. Taken together, the combination of orthogonal information sources led to investigation of a surprising predicted relationship between a transcription factor and an enzyme, specifically, PPARα and the cyclooxygenase enzymes.
These predictions were confirmed by direct biochemical experiments which validate the approach and show for the first time that PPARα agonists are cyclooxygenase inhibitors.
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