7laf | pdb_00007laf
15-lipoxygenase-2 loop mutant bound to imidazole-based inhibitor
Structural highlights
FunctionLX15B_HUMAN Non-heme iron-containing dioxygenase that catalyzes the stereo-specific peroxidation of free and esterified polyunsaturated fatty acids generating a spectrum of bioactive lipid mediators. Converts arachidonic acid to 15S-hydroperoxyeicosatetraenoic acid/(15S)-HPETE. Also acts on linoleic acid to produce 13-hydroxyoctadecadienoic acid/13-HPODE. Has no detectable 8S-lipoxygenase activity but reacts with (8S)-HPETE to produce (8S,15S)-diHPETE. May regulate progression through the cell cycle and cell proliferation. May also regulate cytokine secretion by macrophages and therefore play a role in the immune response. May also regulate macrophages differentiation into proatherogenic foam cells.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedHuman epithelial 15-lipoxygenase-2 (h15-LOX-2, ALOX15B) is expressed in many tissues and has been implicated in atherosclerosis, cystic fibrosis and ferroptosis. However, there are few reported potent/selective inhibitors that are active ex vivo. In the current work, we report newly discovered molecules that are more potent and structurally distinct from our previous inhibitors, MLS000545091 and MLS000536924 (Jameson et al, PLoS One, 2014, 9, e104094), in that they contain a central imidazole ring, which is substituted at the 1-position with a phenyl moiety and with a benzylthio moiety at the 2-position. The initial three molecules were mixed-type, non-reductive inhibitors, with IC50 values of 0.34+/-0.05muM for MLS000327069, 0.53+/-0.04muM for MLS000327186 and 0.87+/-0.06muM for MLS000327206 and greater than 50-fold selectivity versus h5-LOX, h12-LOX, h15-LOX-1, COX-1 and COX-2. A small set of focused analogs was synthesized to demonstrate the validity of the hits. In addition, a binding model was developed for the three imidazole inhibitors based on computational docking and a co-structure of h15-LOX-2 with MLS000536924. Hydrogen/deuterium exchange (HDX) results indicate a similar binding mode between MLS000536924 and MLS000327069, however, the latter restricts protein motion of helix-alpha2 more, consistent with its greater potency. Given these results, we designed, docked, and synthesized novel inhibitors of the imidazole scaffold and confirmed our binding mode hypothesis. Importantly, four of the five inhibitors mentioned above are active in an h15-LOX-2/HEK293 cell assay and thus they could be important tool compounds in gaining a better understanding of h15-LOX-2's role in human biology. As such, a suite of similar pharmacophores that target h15-LOX-2 both in vitro and ex vivo are presented in the hope of developing them as therapeutic agents. Kinetic and structural investigations of novel inhibitors of human epithelial 15-lipoxygenase-2.,Tsai WC, Gilbert NC, Ohler A, Armstrong M, Perry S, Kalyanaraman C, Yasgar A, Rai G, Simeonov A, Jadhav A, Standley M, Lee HW, Crews P, Iavarone AT, Jacobson MP, Neau DB, Offenbacher AR, Newcomer M, Holman TR Bioorg Med Chem. 2021 Sep 15;46:116349. doi: 10.1016/j.bmc.2021.116349. Epub 2021, Aug 5. PMID:34500187[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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