7lag

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CRYSTAL STRUCTURE OF MYELOPEROXIDASE SUBFORM C (MPO) COMPLEX WITH Compound-14 AKA 7-({1-[(3-phenoxyphenyl)methyl]-1H-pyrazol-4-yl}methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine

Structural highlights

7lag is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.85Å
Ligands:BMA, CA, CL, FUC, HEM, MAN, NAG, XSD
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PERM_HUMAN Defects in MPO are the cause of myeloperoxidase deficiency (MPOD) [MIM:254600. A disorder characterized by decreased myeloperoxidase activity in neutrophils and monocytes that results in disseminated candidiasis.[1] [2] [3] [4] [5]

Function

PERM_HUMAN Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance PMN microbicidal activity.

Publication Abstract from PubMed

Myeloperoxidase (MPO), a critical enzyme in antimicrobial host-defense, has been implicated in chronic inflammatory diseases such as coronary artery disease. The design and evaluation of MPO inhibitors for the treatment of cardiovascular disease are reported herein. Starting with the MPO and triazolopyridine 3 crystal structure, novel inhibitors were designed incorporating a substituted pyrazole, which allowed for substituents to interact with hydrophobic and hydrophilic patches in the active site. SAR exploration of the substituted pyrazoles led to piperidine 17, which inhibited HOCl production from activated neutrophils with an IC(50) value of 2.4 muM and had selectivity against thyroid peroxidase (TPO). Optimization of alkylation chemistry on the pyrazole nitrogen facilitated the preparation of many analogs, including macrocycles designed to bridge two hydrophobic regions of the active site. Multiple macrocyclization strategies were pursued to prepare analogs that optimally bound to the active site, leading to potent macrocyclic MPO inhibitors with TPO selectivity, such as compound 30.

Small molecule and macrocyclic pyrazole derived inhibitors of myeloperoxidase (MPO).,Hu CH, Neissel Valente MW, Halpern OS, Jusuf S, Khan JA, Locke GA, Duke GJ, Liu X, Duclos FJ, Wexler RR, Kick EK, Smallheer JM Bioorg Med Chem Lett. 2021 Jun 15;42:128010. doi: 10.1016/j.bmcl.2021.128010. , Epub 2021 Apr 1. PMID:33811992[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
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Anti-inflammatory potential of some eudesmanolide and guaianolide sesquiterpenes.
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See Also

References

  1. ↑ Kizaki M, Miller CW, Selsted ME, Koeffler HP. Myeloperoxidase (MPO) gene mutation in hereditary MPO deficiency. Blood. 1994 Apr 1;83(7):1935-40. PMID:8142659
  2. ↑ Nauseef WM, Brigham S, Cogley M. Hereditary myeloperoxidase deficiency due to a missense mutation of arginine 569 to tryptophan. J Biol Chem. 1994 Jan 14;269(2):1212-6. PMID:7904599
  3. ↑ Nauseef WM, Cogley M, McCormick S. Effect of the R569W missense mutation on the biosynthesis of myeloperoxidase. J Biol Chem. 1996 Apr 19;271(16):9546-9. PMID:8621627
  4. ↑ DeLeo FR, Goedken M, McCormick SJ, Nauseef WM. A novel form of hereditary myeloperoxidase deficiency linked to endoplasmic reticulum/proteasome degradation. J Clin Invest. 1998 Jun 15;101(12):2900-9. PMID:9637725 doi:10.1172/JCI2649
  5. ↑ Romano M, Dri P, Dadalt L, Patriarca P, Baralle FE. Biochemical and molecular characterization of hereditary myeloperoxidase deficiency. Blood. 1997 Nov 15;90(10):4126-34. PMID:9354683
  6. ↑ Hu CH, Neissel Valente MW, Halpern OS, Jusuf S, Khan JA, Locke GA, Duke GJ, Liu X, Duclos FJ, Wexler RR, Kick EK, Smallheer JM. Small molecule and macrocyclic pyrazole derived inhibitors of myeloperoxidase (MPO). Bioorg Med Chem Lett. 2021 Jun 15;42:128010. PMID:33811992 doi:10.1016/j.bmcl.2021.128010

Contents


PDB ID 7lag

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