title: Homology model adjustment and ligand screening with a pseudoreceptor of the human histamine H4 receptor.
abstract: A computer-assisted method for the generation of pseudoreceptor models is presented together with two practical applications. From a three-dimensional alignment of known histamine H(4) receptor ligands, a pseudoreceptor model of the putative ligand binding site was constructed and used for virtual screening of a large collection of commercially available compounds. Two bioactive chemotypes were retrieved, demonstrating the general applicability of the approach. The pseudoreceptor model was also used to find the putative ligand binding pocket within the transmembrane receptor domain. For each frame of a molecular dynamics simulation of a homology-based H(4) receptor model, we automatically extracted potential ligand binding pockets and used their compatibility with the pseudoreceptor as a selection criterion. The best-matching pocket fits perfectly with existing mutation data and previously published hypotheses suggesting Glu182(5.46) as the preferred binding partner of a positively charged moiety of H(4) receptor ligands. This new pseudoreceptor approach has demonstrated its suitability for both structure-based prioritization of protein receptor models, and ligand-based virtual screening with the aim to perform scaffold hopping.
authors.affiliation: Chem- and Bioinformatics LiFF/ZAFES/CMP, Johann Wolfgang Goethe University, Siesmayerstr. 70, 60323 Frankfurt a.M., Germany.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Tanrikulu
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
authors.forename: Tim
authors.initials: T
authors.lastname: Werner
authors.forename: Tim
authors.initials: T
authors.lastname: Geppert
authors.forename: Nickolay
authors.initials: N
authors.lastname: Todoroff
authors.forename: Alexander
authors.initials: A
authors.lastname: Klenner
authors.forename: Tim
authors.initials: T
authors.lastname: Kottke
authors.forename: Kerstin
authors.initials: K
authors.lastname: Sander
authors.forename: Erich
authors.initials: E
authors.lastname: Schneider
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.forename: Timothy
authors.initials: T
authors.lastname: Clark
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider