Dynamic modeling of human 5-lipoxygenase-inhibitor interactions helps to discover novel inhibitors.

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Wu Y, He C, Gao Y, He S, Liu Y, Lai L

Dynamic modeling of human 5-lipoxygenase-inhibitor interactions helps to discover novel inhibitors.

J Med Chem. 2012 Mar 22;55(6):2597-605. doi: 10.1021/jm201497k. Epub 2012 Mar 1.

PubMed ID
22380511 [ View in PubMed
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Abstract

Human 5-lipoxygenase (5-LOX) is one of the key anti-inflammatory drug targets due to its key role in leukotrienes biosynthesis. We have built a model for the active conformation of human 5-LOX using comparative modeling, docking of known inhibitors, and molecular dynamics simulation. Using this model, novel 5-LOX inhibitors were identified by virtual screen. Of the 105 compounds tested in a cell-free assay, 30 have IC(50) values less than 100 muM and 11 less than 10 muM with the strongest inhibition of 620 nM. Compounds 4, 7, and 11 showed strong inhibition activity in the human whole blood (HWB) assay with IC(50) values of 8.6, 9.7, 8.1 muM, respectively. Moreover, compounds 4 and 7 were also found to inhibit microsomal prostaglandin E synthase (mPGES)-1 with micromolar IC(50) values, similar to licofelone, a dual functional inhibitor of 5-LOX/mPGES-1. The compounds reported here provide new scaffolds for anti-inflammatory drug design.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
LicofeloneArachidonate 5-lipoxygenaseIC 50 (nM)180N/AN/ADetails
ZileutonArachidonate 5-lipoxygenaseIC 50 (nM)500N/AN/ADetails
ZileutonArachidonate 5-lipoxygenaseIC 50 (nM)3300N/AN/ADetails
ZileutonArachidonate 5-lipoxygenaseIC 50 (nM)1110N/AN/ADetails