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Novel human lipoxygenase inhibitors discovered using virtual screening with homology models.

Abstract：

: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 microM 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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Kenyon V,Chorny I,Carvajal WJ,Holman TR,Jacobson MP

doi

10.1021/jm050639j

keywords:

subject

Has Abstract

pub_date

2006-02-23 00:00:00

pages

1356-63

issue

4

eissn

0022-2623

issn

1520-4804

journal_volume

49

pub_type

杂志文章

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