title: PENG: a neural gas-based approach for pharmacophore elucidation. method design, validation, and virtual screening for novel ligands of LTA4H.
abstract: 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.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University , 60438 Frankfurt, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Moser
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Wittmann
authors.forename: Jan
authors.initials: J
authors.lastname: Kramer
authors.forename: René
authors.initials: R
authors.lastname: Blöcher
authors.forename: Janosch
authors.initials: J
authors.lastname: Achenbach
authors.forename: Denys
authors.initials: D
authors.lastname: Pogoryelov
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
mesh_terms: D000465:Algorithms; D000626:Aminopeptidases / Q000737:chemistry; D019985:Benchmarking; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D016571:Neural Networks, Computer; D011446:Prospective Studies; D011485:Protein Binding; D015203:Reproducibility of Results; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D004851:Epoxide Hydrolases; D000626:Aminopeptidases; C043134:leukotriene A4 hydrolase