Document Detail

Identification of Purple Acid Phosphatase Inhibitors by Fragment-Based Screening: Promising New Leads for Osteoporosis Therapeutics.
MedLine Citation:
PMID:  22943065     Owner:  NLM     Status:  Publisher    
Purple acid phosphatases 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 purple acid phosphatases 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 purple acid phosphatases 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 purple acid phosphatases (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 purple acid phosphatases. These studies open the way to the design of more potent and selective inhibitors of purple acid phosphatases that can be tested as anti-osteoporotic drug leads.
Daniel Feder; Waleed M Hussein; Daniel J Clayton; Meng-Wei Kan; Gerhard Schenk; Ross P McGeary; Luke W Guddat
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-9-3
Journal Detail:
Title:  Chemical biology & drug design     Volume:  -     ISSN:  1747-0285     ISO Abbreviation:  Chem Biol Drug Des     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-9-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101262549     Medline TA:  Chem Biol Drug Des     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2012 John Wiley & Sons A/S.
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Qld 4072, Australia Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein Helwan, Helwan, Egypt Department of Chemistry, National University of Ireland - Maynooth, Maynooth, Co. Kildare, Ireland School of Pharmacy, The University of Queensland, Brisbane, Qld 4072, Australia.
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