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Chem Biol Drug Des. 2012 Jul 12. doi: 10.1111/j.1747-0285.2012.12001.x. [Epub ahead of print]

Identification of purple acid phosphatase inhibitors by fragment-based screening: Promising new leads for osteoporosis therapeutics.

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  • 1The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Qld 4072, Australia Helwan University, Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Ein Helwan, Helwan, Egypt National University of Ireland - Maynooth, Department of Chemistry, Maynooth, Co. Kildare, Ireland The University of Queensland, School of Pharmacy, Brisbane, Qld 4072, Australia.

Abstract

Purple acid phosphatases (PAPs) are metalloenzymes found in animals, plants and fungi. They possess a binuclear metal centre to catalyse the hydrolysis of phosphate esters and anhydrides under acidic conditions. In humans, elevated PAP levels in sera are correlated with the progression of osteoporosis and metabolic bone malignancies, making this enzyme a target for the development of new chemotherapeutics to treat bone-related illnesses. To date, little progress has been achieved towards the design of specific and potent inhibitors of this enzyme that have drug-like properties. Here, we have undertaken a fragment-based screening approach using a 500-compound library identifying three inhibitors of PAP with K(i) values in the 30 - 60 μM range. Ligand efficiency values are 0.39-0.44 kcal/mol per heavy atom. X-ray crystal structures of these compounds in complex with a plant PAP (2.3-2.7 Å resolution) have been determined and show that all bind in the active site within contact of the binuclear centre. For one of these compounds, the phenyl ring is positioned within 3.5 Å of the binuclear centre. Docking simulations indicate that the three compounds fit into the active site of human PAP. These studies open the way to the design of more potent and selective inhibitors of PAPs that can be tested as anti-osteoporotic drug leads. © 2012 John Wiley & Sons A/S.

© 2012 John Wiley & Sons A/S.

PMID:
22788702
[PubMed - as supplied by publisher]
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