7LAF

15-lipoxygenase-2 loop mutant bound to imidazole-based inhibitor

7LAF の概要

• エントリーDOI: 10.2210/pdb7laf/pdb
• 分子名称: Polyunsaturated fatty acid lipoxygenase ALOX15B, MANGANESE (II) ION, 3-{[(4-methylphenyl)methyl]sulfanyl}-1-phenyl-1H-1,2,4-triazole, ... (4 entities in total)
• 機能のキーワード: lipoxygenase, inhibitor, allostery, complex, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, lipid binding protein, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 155422.47

構造登録者

Newcomer, M.E.,Gilbert, N.C.,Neau, D.B. (登録日: 2021-01-06, 公開日: 2022-01-19, 最終更新日: 2023-10-18)

主引用文献

Tsai, W.C.,Gilbert, N.C.,Ohler, A.,Armstrong, M.,Perry, S.,Kalyanaraman, C.,Yasgar, A.,Rai, G.,Simeonov, A.,Jadhav, A.,Standley, M.,Lee, H.W.,Crews, P.,Iavarone, A.T.,Jacobson, M.P.,Neau, D.B.,Offenbacher, A.R.,Newcomer, M.,Holman, T.R.
Kinetic and structural investigations of novel inhibitors of human epithelial 15-lipoxygenase-2.
Bioorg.Med.Chem., 46:116349-116349, 2021

PubMed Abstract: Human 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 IC values of 0.34 ± 0.05 μM for MLS000327069, 0.53 ± 0.04 μM for MLS000327186 and 0.87 ± 0.06 μM 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-α2 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.

PubMed: 34500187
DOI: 10.1016/j.bmc.2021.116349

実験手法

X-RAY DIFFRACTION (2.44 Å)