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J Med Chem. 2012 Aug 23;55(16):7054-60. doi: 10.1021/jm300671m. Epub 2012 Aug 6.

Shape-based reprofiling of FDA-approved drugs for the H₁ histamine receptor.

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Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, United Kingdom.


Reprofiling of existing drugs to treat conditions not originally targeted is an attractive means of addressing the problem of a decreasing stream of approved drugs. To determine if 3D shape similarity can be used to rationalize an otherwise serendipitous process, we employed 3D shape-based virtual screening to reprofile existing FDA-approved drugs. The study was conducted in two phases. First, multiple histamine H(1) receptor antagonists were identified to be used as query molecules, and these were compared to a database of approved drugs. Second, the hits were ranked according to 3D similarity and the top drugs evaluated in a cell-based assay. The virtual screening methodology proved highly successful, as 13 of 23 top drugs tested selectively inhibited histamine-induced calcium release with the best being chlorprothixene (IC(50) 1 nM). Finally, we confirmed that the drugs identified using the cell-based assay were all acting at the receptor level by conducting a radioligand-binding assay using rat membrane.

[Indexed for MEDLINE]

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