alexa From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists | OMICS International | Abstract
ISSN: 2161-0444

Medicinal Chemistry
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Research Article

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

Alexander Heifetz1*, Michael P Mazanetz1, Tim James1, Sandeep Pal1, Richard J Law1, Mark Slack2 and Philip C Biggin3

1Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK

2Evotec AG, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany

3Department of Biochemistry, University of Oxford, South Parks Road Oxford OX1 3QU, UK

*Corresponding Author:
Alexander Heifetz
Evotec (UK) Ltd., 114 Innovation Drive
Milton Park, Abingdon
Oxfordshire OX14 4RZ, UK
Tel: +44 1235 838925
Fax: +44 1235 863139
E-mail: [email protected]

Received date: November 27, 2013; Accepted date: December 24, 2013; Published date: December 27, 2013

Citation: Heifetz A, Mazanetz MP, James T, Pal S, Law RJ, et al. (2013) From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists. Med chem 4:313-321. doi: 10.4172/2161-0444.1000158

Copyright: © 2013 Heifetz A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

G-Protein Coupled Receptors (GPCRs) have enormous physiological and biomedical importance, being the primary target of a large number of modern drugs. The availability of structural information of the binding site of the targeted GPCR plays a key role in rationalization, efficiency and cost-effectiveness of the drug discovery process. However, obtaining structural information on GPCRs using X-ray crystallography or NMR requires a large investment of time and is technically very challenging. This situation significantly limits the ability of these methods to have an impact in drug discovery for GPCR targets in the short term and hence there is an urgent need for other effective and cost-efficient alternatives. We present here a practical approach that integrates GPCR modelling with fragment based screening to provide structural insights on the H3 and H4 histamine receptor binding sites. This approach creates a cost-efficient new avenue for structure-based drug design (SBDD) against GPCR targets. We report here a success of using this protocol for the discovery of selective and dual H3 and H4 antagonists. Our fragment screen yielded 44 H3, 21 H4 selective and 20 dual fragment hits. These fragments were used to construct high- quality H3 and H4 models followed by binding site exploration and structure based virtual screening (VS). Overall, 172 compounds were purchased for testing based on the virtual screening results. Of the 74 compounds predicted to have dual activity, 33 had activity against one or other of the two receptors (44%), of which 17 had activity against both. Of the 19 compounds predicted to be H3 selective, 13 were active against H3 (68%) and 10 of these also had selectivity over H4. Of the 79 compounds predicted to be H4 selective, 36 were active against H4 (45%) and 2 of these also had selectivity over H3

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