Shape-based reprofiling of FDA-approved drugs for the H₁ histamine receptor.
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 s...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2012
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| _version_ | 1797060816909893632 |
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| author | Vasudevan, SR Moore, J Schymura, Y Churchill, G |
| author_facet | Vasudevan, SR Moore, J Schymura, Y Churchill, G |
| author_sort | Vasudevan, SR |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T20:22:16Z |
| format | Journal article |
| id | oxford-uuid:2e37c0c0-5f9a-4d5c-a500-ac13e69d8798 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:22:16Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:2e37c0c0-5f9a-4d5c-a500-ac13e69d87982022-03-26T12:47:40ZShape-based reprofiling of FDA-approved drugs for the H₁ histamine receptor.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2e37c0c0-5f9a-4d5c-a500-ac13e69d8798EnglishSymplectic Elements at Oxford2012Vasudevan, SRMoore, JSchymura, YChurchill, GReprofiling 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. |
| spellingShingle | Vasudevan, SR Moore, J Schymura, Y Churchill, G Shape-based reprofiling of FDA-approved drugs for the H₁ histamine receptor. |
| title | Shape-based reprofiling of FDA-approved drugs for the H₁ histamine receptor. |
| title_full | Shape-based reprofiling of FDA-approved drugs for the H₁ histamine receptor. |
| title_fullStr | Shape-based reprofiling of FDA-approved drugs for the H₁ histamine receptor. |
| title_full_unstemmed | Shape-based reprofiling of FDA-approved drugs for the H₁ histamine receptor. |
| title_short | Shape-based reprofiling of FDA-approved drugs for the H₁ histamine receptor. |
| title_sort | shape based reprofiling of fda approved drugs for the h₁ histamine receptor |
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