PENG: A Neural Gas-Based Approach for Pharmacophore Elucidation. Method Design, Validation, and Virtual Screening for Novel Ligands of LTA4H

The pharmacophore concept is commonly employed in virtual screening for hit identification. A pharmacophore is generally defined as the three-dimensional arrangement of the structural and physicochemical features of a compound responsible for its affinity to a pharmacological target. Given a number...

Full description

Saved in:
Bibliographic Details
Published in:Journal of chemical information and modeling 2015-02, Vol.55 (2), p.284-293
Main Authors: Moser, Daniel, Wittmann, Sandra K, Kramer, Jan, Blöcher, René, Achenbach, Janosch, Pogoryelov, Denys, Proschak, Ewgenij
Format: Article
Language:English
Subjects:
Algorithms
Aminopeptidases - chemistry
Benchmarking
Chemical compounds
Crystallography, X-Ray
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Enzyme kinetics
Epoxide Hydrolases - antagonists & inhibitors
Epoxide Hydrolases - chemistry
High-Throughput Screening Assays - methods
Humans
Ligands
Models, Molecular
Molecular structure
Molecules
Neural Networks (Computer)
Pharmacology
Prospective Studies
Protein Binding
Reproducibility of Results
Thermodynamics
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The pharmacophore concept is commonly employed in virtual screening for hit identification. A pharmacophore is generally defined as the three-dimensional arrangement of the structural and physicochemical features of a compound responsible for its affinity to a pharmacological target. Given a number of active ligands binding to a particular target in the same manner, it can reasonably be assumed that they have some shared features, a common pharmacophore. We present a growing neural gas (GNG)-based approach for the extraction of the relevant features which we called PENG (pharmacophore elucidation by neural gas). Results of retrospective validation indicate an acceptable quality of the generated models. Additionally a prospective virtual screening for leukotriene A4 hydrolase (LTA4H) inhibitors was performed. LTA4H is a bifunctional zinc metalloprotease which displays both epoxide hydrolase and aminopeptidase activity. We could show that the PENG approach is able to predict the binding mode of the ligand by X-ray crystallography. Furthermore, we identified a novel chemotype of LTA4H inhibitors.
ISSN:1549-9596
1549-960X
DOI:10.1021/ci500618u