8brn

Crystal structure of red kidney bean purple acid phosphatase in complex with an alpha-aminonaphthylmethylphosphonic acid inhibitor

spinqualitylabelsall models 8brn, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8brn is a 4 chain structure with sequence from Phaseolus vulgaris. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2Å Ligands: BMA, CL, DMS, EDO, FE, FLC, FUC, GOL, MAN, NA, NAG, PGE, R9X, SO4, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PPAF_PHAVU Publication Abstract from PubMed Purple acid phosphatases (PAPs) are ubiquitous binuclear metallohydrolases that have been isolated from various animals, plants and some types of fungi. In humans and mice, elevated PAP activity in osteoclasts is associated with osteoporosis, making human PAP an attractive target for the development of anti-osteoporotic drugs. Based on previous studies focusing on phosphonate scaffolds, as well as a new crystal structure of a PAP in complex with a derivative of a previously synthesized alpha-aminonaphthylmethylphosphonic acid, phosphonates 24-40 were designed as new PAP inhibitor candidates. Subsequent docking studies predicted that all of these compounds are likely to interact strongly with the active site of human PAP and most are likely to interact strongly with the active site of pig PAP. The seventeen candidates were synthesized with good yields and nine of them (26-28, 30, 33-36 and 38) inhibit in the sub-micromolar to nanomolar range against pig PAP, with 28 and 35 being the most potent mammalian PAP inhibitors reported with K(i) values of 168 nM and 186 nM, respectively. This study thus paves the way for the next stage of drug development for phosphonate inhibitors of PAPs as anti-osteoporotic agents. Optimization of an alpha-aminonaphthylmethylphosphonic acid inhibitor of purple acid phosphatase using rational structure-based design approaches.,Feder D, Mohd-Pahmi SH, Adibi H, Guddat LW, Schenk G, McGeary RP, Hussein WM Eur J Med Chem. 2023 Jun 5;254:115383. doi: 10.1016/j.ejmech.2023.115383. Epub , 2023 Apr 16. PMID:37087894 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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