Shape-Based Reprofiling of FDA-Approved Drugs for the H 1 Histamine Receptor Sridhar R. Vasudevan,* ,† John B. Moore, † Yves Schymura, and Grant C. Churchill Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, United Kingdom * S Supporting Information 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. ■ INTRODUCTION In light of the increasing costs of drug development and ever- decreasing stream of newly approved drugs, finding novel uses for existing drugs is rapidly gaining popularity. This process, termed reprofiling (also known as redirecting, repositioning, or repurposing), 1 has several advantages over de novo drug development. The expedited bench-to-clinic translation and the potential to address serious illnesses for which treatments have not been developed are unparalleled by any alternative drug discovery approach. Several examples of successful reprofiling exist. 1 Miltefosine, for example, failed phase II clinical trials for tumor reduction but was later discovered to possess anti-infective properties in in vitro and in vivo studies and subsequently passed clinical trials for treating visceral leishmaniasis. 2 Given the vast potential of reprofiling, several approaches are being taken to move reprofiling finds from those of a serendipitous nature to a rational scientific discovery. These include approaches based on transcriptional responses, 3 medicinal chemistry, 4 chemoinfor- matics, 5 chemical genomics, 6 side effect similarity, 7 molecular topology, 8 and phenotypic screening. 9 Although effective, these approaches require much effort and expertise. To date, a few computational methods have been described to be of use in reprofiling and to predict adverse drug reactions. These include structure-based approaches such as molecular docking, 10 ligand-based chemoinformatic approaches such as SEA, 5b bayesian models, 6b and FEPOPS descriptors. 5b However, to our knowledge, no study has employed a pure 3D shape-based screening method for reprofiling. As some compounds that do not appear to have commonality in their 2D chemical scaffold will overlap significantly in three-dimensional space and possess similar bioactivity, 11 we determined if 3D shape comparisons can be used as a meaningful method to search for drug activity within the FDA-approved drug database. In order to explore this idea, we compared the shape characteristics of H 1 antihistamines with a database of FDA-approved drugs to identify drugs with previously unknown antihistamine activity. The shape-based screening was not only accurate in picking many of the previously reported drugs that acted on H 1 receptors but also identified drugs including those previously not reported to act on these receptors. These results demonstrate the validity of using a simple measure such as 3D shape similarity in uncovering previously unknown drug activity. ■ RESULTS AND DISCUSSION Our aim was to test if computational shape-based screening could be used to predict the additional effects that a drug might have on targets not originally known, antihistamine activity in this instance. In order to test this hypothesis, we compared the shape characteristics of H 1 antihistamines with a database of 1216 FDA-approved drugs from the U.S. Environmental Protection Agency’s DSStox public database. 12 The H 1 receptor was chosen because of a large body of information detailing the actions of various other pharmaceutical agents on this target, which in turn would allow us to validate our results. The FDA database was chosen as it consists of compounds with well-characterized activity in established drug classes, which would allow us to convey more concretely the degree of enrichment the virtual Received: March 13, 2012 Published: July 13, 2012 Article pubs.acs.org/jmc © 2012 American Chemical Society 7054 dx.doi.org/10.1021/jm300671m | J. Med. Chem. 2012, 55, 7054-7060