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 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.
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, United Kingdom. sridhar.vasudevan@pharm.ox.ac.uk
Sridhar R
SR
Vasudevan
John B
JB
Moore
Yves
Y
Schymura
Grant C
GC
Churchill
D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002749:Chlorprothixene / Q000737:chemistry / Q000494:pharmacology; D062126:Databases, Chemical; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014481:United States; D014486:United States Food and Drug Administration
D000928:Antidepressive Agents; D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D006632:Histamine; D002749:Chlorprothixene; D002118:Calcium