Detecting Drug Promiscuity Using Gaussian Ensemble Screening

Violeta Pérez-Nueno 1 Vishwesh Venkatraman 1 Lazaros Mavridis 1 David Ritchie 1
1 ORPAILLEUR - Knowledge representation, reasonning
Inria Nancy - Grand Est, LORIA - NLPKD - Department of Natural Language Processing & Knowledge Discovery
Abstract : Polypharmacology describes the binding of a ligand to multiple protein targets (a promiscuous ligand) or multiple diverse ligands binding to a given target (a promiscuous target). Pharmaceutical companies are discovering increasing numbers of both promiscuous drugs and drug targets. Hence, polypharmacology is now recognized as an important aspect of drug design. Here, we describe a new and fast way to predict polypharmacological relationships between drug classes quantitatively, which we call Gaussian Ensemble Screening (GES). This approach represents a cluster of molecules with similar spherical harmonic surface shapes as a Gaussian distribution with respect to a selected center molecule. Calculating the Gaussian overlap between pairs of such clusters allows the similarity between drug classes to be calculated analytically without requiring thousands of bootstrap comparisons, as in current promiscuity prediction approaches. We find that such cluster similarity scores also follow a Gaussian distribution. Hence, a cluster similarity score may be transformed into a probability value, or "p-value", in order to quantify the relationships between drug classes. We present results obtained when using the GES approach to predict relationships between drug classes in a subset of the MDL Drug Data Report (MDDR) database. Our results indicate that GES is a useful way to study polypharmacology relationships, and it could provide a novel way to propose new targets for drug repositioning.
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https://hal.inria.fr/hal-00756804
Contributor : David Ritchie <>
Submitted on : Friday, November 23, 2012 - 5:29:00 PM
Last modification on : Tuesday, December 18, 2018 - 4:38:02 PM

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Violeta Pérez-Nueno, Vishwesh Venkatraman, Lazaros Mavridis, David Ritchie. Detecting Drug Promiscuity Using Gaussian Ensemble Screening. Journal of Chemical Information and Modeling, American Chemical Society, 2012, 52 (8), pp.1948-1961. ⟨10.1021/ci3000979⟩. ⟨hal-00756804⟩

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