8BRN

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

Summary for 8BRN

• Entry DOI: 10.2210/pdb8brn/pdb
• Descriptor: Fe(3+)-Zn(2+) purple acid phosphatase, alpha-L-fucopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose, ZINC ION, ... (23 entities in total)
• Functional Keywords: metallohydrolase, phosphatase, metal binding protein
• Biological source: Phaseolus vulgaris
• Total number of polymer chains: 4
• Total formula weight: 226076.82

Authors

Feder, D.,Hussein, W.M.,Guddat, L.W.,Schenk, G. (deposition date: 2022-11-23, release date: 2023-08-02, Last modification date: 2024-10-16)

Primary citation

Feder, D.,Mohd-Pahmi, S.H.,Adibi, H.,Guddat, L.W.,Schenk, G.,McGeary, R.P.,Hussein, W.M.
Optimization of an alpha-aminonaphthylmethylphosphonic acid inhibitor of purple acid phosphatase using rational structure-based design approaches.
Eur.J.Med.Chem., 254:115383-115383, 2023

PubMed Abstract: 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 α-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 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.

PubMed: 37087894
DOI: 10.1016/j.ejmech.2023.115383

Experimental method

X-RAY DIFFRACTION (2 Å)