Identification of natural-product-derived inhibitors of 5-lipoxygenase activity by ligand-based virtual screening.
A natural product collection and natural-product-derived combinatorial libraries were virtually screened for potential inhibitors of human 5-lipoxygenase (5-LO) activity. We followed a sequential ligand-based approach in two steps. First, similarity searching with a topological pharmacophore descriptor (CATS 2D method) was performed to enable scaffold-hopping. Eighteen compounds were selected from a virtual hit list of 430 substances, which had mutual pharmacophore features with at least one of 43 known 5-LO inhibitors that served as query structures. Two new chemotypes exhibited significant activity in a cell-based 5-LO activity assay. The two most potent molecules served as seed structures for a second virtual screening round. This time, a focused natural-product-derived combinatorial library was analyzed by different ligand-based virtual screening methods. The best molecules from the final set of screening candidates potently suppressed 5-LO activity in intact cells and may represent a novel class of 5-LO inhibitors. The results demonstrate the potential of natural-product-derived screening libraries for hit and lead structure identification.
Franke
Lutz
L
Institut für Organische Chemie und Chemische Biologie/ZAFES, Johann Wolfgang Goethe-Universität, Siesmayerstrasse 70, D-60323 Frankfurt am Main, Germany.
Schwarz
Oliver
O
Müller-Kuhrt
Lutz
L
Hoernig
Christina
C
Fischer
Lutz
L
George
Sven
S
Tanrikulu
Yusuf
Y
Schneider
Petra
P
Werz
Oliver
O
Steinhilber
Dieter
D
Schneider
Gisbert
G
D000328:Adult; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry*; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology; D002474:Cell-Free System; D016208:Databases, Factual; D006801:Humans; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors; D008958:Models, Molecular; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology
D001688:Biological Products; D016859:Lipoxygenase Inhibitors; D011725:Pyridines; D013764:Tetrahydronaphthalenes; D013844:Thiazoles; D013876:Thiophenes; D001094:Arachidonate 5-Lipoxygenase