TY  - CONF
A1  - Moser, Daniel
A1  - Wisniewska, Joanna Marta
A1  - Hahn, Steffen
A1  - Buscató, Estel la
A1  - Klingler, Franca-Maria
A1  - Achenbach, Janosch
A1  - Hofmann, Bettina
A1  - Steinhilber, Dieter
A1  - Proschak, Ewgenij
T1  - Design of dual ligands using excessive pharmacophore query alignment : from 7th German Conference on Chemoinformatics: 25 CIC-Workshop Goslar, Germany, 6 - 8 November 2011
T2  - Journal of cheminformatics
N2  - Dual- or multi-target ligands have gained increased attention in the past years due to several advantages, including more simple pharmacokinetic and phamarcodynamic properties compared to a combined application of several drugs. Furthermore multi-target ligands often possess improved efficacy. We present a new approach for the discovery of dual-target ligands using aligned pharmacophore models combined with a shape-based scoring. Starting with two sets of known active compounds for each target, a number of different pharmacophore models is generated and subjected to pairwise graph-based alignment using the Kabsch-Algorithm. Since a compound may be able to bind to different targets in different conformations, the algorithm aligns pairs of pharmacophore models sharing the same features which are not necessarily at the exactly same spatial distance. Using the aligned models, a pharmacophore search on a multi-conformation-database is performed to find compounds matching both models. The potentially “dual” ligands are scored by a shape-based comparison with the known active molecules using ShaEP.
Using this approach, we performed a prospective fragment-based virtual screening for dual 5-LO/sEH inhibitors. Both enzymes play an important role in the arachidonic acid cascade and are involved in inflammatory processes, pain, cardiovascular diseases and allergic reactions. Beside several new selective inhibitors we were able to find a compound inhibiting both enzymes in low micromolar concentrations. The results indicate that the idea of aligned pharmacophore models can be successfully employed for the discovery of dual-target ligands.
Y1  - 2012
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/27236
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-272361
SN  - 1758-2946
N1  - © 2012 Moser et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
VL  - 4
IS  - (Suppl 1):O11
PB  - BioMed Central
CY  - London
ER  -