Novel Human Lipoxygenase Inhibitors Discovered Using Virtual Screening with Homology Models

We report the discovery of new, low micromolar, small molecule inhibitors of human platelet-type 12- and
reticulocyte 15-lipoxygenase-1 (12-hLO and 15-hLO) using structure-based methods. Specifically, we created
homology models of 12-hLO and 15-hLO, based on the structure of rabbit 15-lipoxygenase, for in silico
screening of a large compound library followed by in vitro screening of 20 top scoring molecules. Eight of
these compounds inhibited either 12- or 15-human lipoxygenase with lower than 100 μM affinity. Of these,
we obtained IC50 values for the three best inhibitors, all of which displayed low micromolar inhibition. One
compound showed specificity for 15-hLO versus 12-hLO; however, a selective inhibitor for 12-hLO was
not identified. As a control we screened 20 randomly selected compounds, of which none showed low
micromolar inhibition. The new low-micromolar inhibitors appear to be suitable as leads for further inhibitor
development efforts against 12-hLO and 15-hLO, based on the fact their size and chemical properties are
appropriate to classify them as drug-like compounds. The models of these protein−inhibitor complexes
suggest strategies for future development of selective lipoxygenase inhibitors.