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

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

Chemical Biology & Drug Design, July 2012

22788702

Daniel Feder, Waleed M. Hussein, Daniel J. Clayton, Meng-Wei Kan, Gerhard Schenk, Ross P. McGeary, Luke W. Guddat

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.