title: Exploring the chemical space of multitarget ligands using aligned self-organizing maps.
abstract: Design of multitarget drugs and polypharmacological compounds has become popular during the past decade. However, the main approach to design such compounds is to link two selective ligands via a flexible linker. Although such chimeric ligands often have reasonable potency in vitro, the in vivo efficacy is low due to high molecular weight, low ligand efficiency, and poor pharmacokinetic profile. We developed an unprecedented in silico approach for fragment-based design of multitarget ligands. It relies on superposition of the chemical spaces related to the affinity on single targets represented by self-organizing maps. We used this approach for screening of molecular fragments, which bind to the enzymes 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH). Using STD-NMR and activity-based assays, we were able to identify fragments binding to both targets. Furthermore, we were able to expand one of the fragments to a potent dual inhibitor bearing a reasonable molecular weight (MW = 446) and high affinity to both targets (IC50 of 0.03 μM toward 5-LO and 0.17 μM toward sEH).
authors.affiliation: Institute of Pharmaceutical Chemistry, ZAFES/OSF, Goethe University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Janosch
authors.initials: J
authors.lastname: Achenbach
authors.affiliation: Institute of Pharmaceutical Chemistry, ZAFES/OSF, Goethe University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Franca-Maria
authors.initials: FM
authors.lastname: Klingler
authors.affiliation: Institute of Pharmaceutical Chemistry, ZAFES/OSF, Goethe University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Blöcher
authors.affiliation: Institute of Pharmaceutical Chemistry, ZAFES/OSF, Goethe University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Moser
authors.affiliation: Institute of Pharmaceutical Chemistry, ZAFES/OSF, Goethe University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Häfner
authors.affiliation: Institute of Pharmaceutical Chemistry, ZAFES/OSF, Goethe University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Carmen B
authors.initials: CB
authors.lastname: Rödl
authors.affiliation: Institute of Pharmaceutical Chemistry, ZAFES/OSF, Goethe University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Kretschmer
authors.affiliation: Chemical R&D-Drug Design, Merz Pharmaceuticals GmbH , Eckenheimer Landstrasse 100, D-60318 Frankfurt, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Krüger
authors.affiliation: Institute of Biophysical Chemistry, Goethe University , Max-von-Laue Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Löhr
authors.affiliation: Institute of Pharmaceutical Chemistry, ZAFES/OSF, Goethe University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.affiliation: Institute of Pharmaceutical Chemistry, ZAFES/OSF, Goethe University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Hofmann
authors.affiliation: Institute of Pharmaceutical Chemistry, ZAFES/OSF, Goethe University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.affiliation: Institute of Pharmaceutical Chemistry, ZAFES/OSF, Goethe University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
keywords: 5-lipoxygenase; Aligned self-organizing maps; soluble epoxide hydrolase; structure−activity relationships