Pseudoreceptor-based pocket selection in a molecular dynamics simulation of the histamine H4 receptor

  • There is a renewed interest in pseudoreceptor models which enable computational chemists to bridge the gap of ligand- and receptor-based drug design. We developed a pseudoreceptor model for the histamine H4 receptor (H4R) based on five potent antagonists representing different chemotypes. Here we present the selection of potential ligand binding pockets that occur during molecular dynamics (MD) simulations of a homology-based receptor model. We present a method for prioritizing receptor models according to their match with the consensus ligand-binding mode represented by the pseudoreceptor. In this way, ligand information can be transferred to receptor-based modelling. We use Geometric Hashing to match three-dimensional points in Cartesion space. This allows for the rapid translation- and rotation-free comparison of atom coordinates, which also permits partial matching. The only prerequisite is a hash table, which uses distance triplets as hash keys. Each time a distance triplet occurring in the candidate point set which corresponds to an existing key, the match is represented by a vote of the respective key. Finally, the global match of both point sets can be easily extracted by selection of voted distance triplets. The results revealed a preferred ligand-binding pocket in H4R, which would not have been identified using an unrefined homology model of the protein. The key idea was to rely on ligand information by pseudoreceptor modelling.

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Author:Tim Werner, Tim Geppert, Yusuf Tanrikulu, Ewgenij ProschakORCiDGND, Gisbert SchneiderORCiDGND
Parent Title (English):Chemistry central journal
Publisher:BioMed Central
Place of publication:London
Document Type:Article
Date of Publication (online):2009/08/26
Date of first Publication:2009/06/05
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Contributing Corporation:4th German Conference on Chemoinformatics Goslar, Germany. 9–11 November 2008
Release Date:2009/08/26
Page Number:1
First Page:1
Last Page:1
© 2009 Werner et al; licensee BioMed Central Ltd.
Source:4th German Conference on Chemoinformatics Goslar, Germany. 9–11 November 2008 ; Chemistry Central Journal 2009, 3(Suppl 1):P74 ; doi:10.1186/1752-153X-3-S1-P74 ;
Institutes:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
Licence (German):License LogoDeutsches Urheberrecht