Shape-based reprofiling of FDA-approved drugs for the H(1) histamine receptor.

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Vasudevan SR, Moore JB, Schymura Y, Churchill GC

Shape-based reprofiling of FDA-approved drugs for the H(1) histamine receptor.

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

PubMed ID
22793499 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
ChlorprothixeneHistamine H1 receptorProteinHumans
Yes
Antagonist
Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
ChlorprothixeneHistamine H1 receptorIC 50 (nM)1N/AN/ADetails
ChlorprothixeneHistamine H1 receptorIC 50 (nM)870.96N/AN/ADetails
MepyramineHistamine H1 receptorIC 50 (nM)46.77N/AN/ADetails
OrphenadrineHistamine H1 receptorIC 50 (nM)97723.72N/AN/ADetails
PromazineHistamine H1 receptorIC 50 (nM)2454.71N/AN/ADetails