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Schwendt, Marek; Dunčko, Roman; Makatsori, Aikaterini; Moncek, Fedor; Johansson, Barbro; Ježová, Daniela

doi:10.1023/a:1022854213991

Cited by 8 publications

(1 citation statement)

References 33 publications

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“…Our first example from above involving the barbiturate GABA A R agonists and SCN antagonists shows a tertiary target overlap in addition to their primary target overlap. The barbiturates phenobarbital and pentobarbital and the SCN antagonists felbamate, phenytoin, and topiramate have been shown to inhibit glutamatergic NMDA receptors. ,− …”

Section: Discussionmentioning

confidence: 99%

Robust Ligand-Based Modeling of the Biological Targets of Known Drugs

Cleves

Jain

2006

J. Med. Chem.

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Systematic annotation of the primary targets of roughly 1000 known therapeutics reveals that over 700 of these modulate approximately 85 biological targets. We report the results of three analyses. In the first analysis, drug/drug similarities and target/target similarities were computed on the basis of three-dimensional ligand structures. Drug pairs sharing a target had significantly higher similarity than drug pairs sharing no target. Also, target pairs with no overlap in annotated drug specificity shared lower similarity than target pairs with increasing overlap. Two-way agglomerative clusterings of drugs and targets were consistent with known pharmacology and suggestive that side effects and drug-drug interactions might be revealed by modeling many targets. In the second analysis, we constructed and tested ligand-based models of 22 diverse targets in virtual screens using a background of screening molecules. Greater than 100-fold enrichment of cognate versus random molecules was observed in 20/22 cases. In the third analysis, selectivity of the models was tested using a background of drug molecules, with selectivity of greater than 80-fold observed in 17/22 cases. Predicted activities derived from crossing drugs against modeled targets identified a number of known side effects, drug specificities, and drug-drug interactions that have a rational basis in molecular structure.

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