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Accession Number ADA571027
Title Exploring Polypharmacology Using a ROCS-Based Target Fishing Approach.
Publication Date 2012
Media Count 16p
Personal Author A. Wallqvist H. Sun M. D. AbdulHameed N. Singh S. Chaudhury
Abstract Polypharmacology has emerged as a new theme in drug discovery. In this paper, we studied polypharmacology using a ligand-based target fishing (LBTF) protocol. To implement the protocol, we first generated a chemogenomic database that links individual protein targets with a specified set of drugs or target representatives. Target profiles were then generated for a given query molecule by computing maximal shape/chemistry overlap between the query molecule and the drug sets assigned to each protein target. The overlap was computed using the program ROCS (Rapid Overlay of Chemical Structures). We validated this approach using the Directory of Useful Decoys (DUD). DUD contains 2950 active compounds, each with 36 property-matched decoys, against 40 protein targets. We chose a set of known drugs to represent each DUD target, and we carried out ligand-based virtual screens using data sets of DUD actives seeded into DUD decoys for each target. We computed Receiver Operator Characteristic (ROC) curves and associated area under the curve (AUC) values. For the majority of targets studied, the AUC values were significantly better than for the case of a random selection of compounds. In a second test, the method successfully identified off-targets for drugs such as rimantadine, propranolol, and domperidone that were consistent with those identified by recent experiments. The results from our ROCS-based target fishing approach are promising and have potential application in drug repurposing for single and multiple targets, identifying targets for orphan compounds, and adverse effect prediction.
Keywords Adverse conditions
Data bases
Multiple targets
Unexploded ammunition

Source Agency Non Paid ADAS
NTIS Subject Category 57Q - Pharmacology & Pharmacological Chemistry
Corporate Author Army Medical Research and Materiel Command (Provisional), Fort Detrick, MD. Telemedicine and Advanced Tech Research Center.
Document Type Journal article
Title Note Journal article.
NTIS Issue Number 1315
Contract Number TMTI0004-09-BH-T

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