title: Penicillin inhibitors of purple acid phosphatase.
abstract: Purple acid phosphatases (PAPs) are binuclear metallohydrolases that have a multitude of biological functions and are found in fungi, bacteria, plants and animals. In mammals, PAP activity is linked with bone resorption and over-expression can lead to bone disorders such as osteoporosis. PAP is therefore an attractive target for the development of drugs to treat this disease. A series of penicillin conjugates, in which 6-aminopenicillanic acid was acylated with aromatic acid chlorides, has been prepared and assayed against pig PAP. The binding mode of most of these conjugates is purely competitive, and some members of this class have potencies comparable to the best PAP inhibitors yet reported. The structurally related penicillin G was shown to be neither an inhibitor nor a substrate for pig PAP. Molecular modelling has been used to examine the binding modes of these compounds in the active site of the enzyme and to rationalise their activities.
authors.affiliation: The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Qld 4072, Australia.
authors.lastname: Faridoon
authors.forename: Waleed M
authors.initials: WM
authors.lastname: Hussein
authors.forename: Nazar
authors.initials: N
authors.lastname: Ul Islam
authors.forename: Luke W
authors.initials: LW
authors.lastname: Guddat
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schenk
authors.forename: Ross P
authors.initials: RP
authors.lastname: McGeary
mesh_terms: D000135:Acid Phosphatase / Q000037:antagonists & inhibitors*; D000146:Acids, Carbocyclic / Q000737:chemistry; D000215:Acylation; D000818:Animals; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001862:Bone Resorption / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control; D020134:Catalytic Domain; D003198:Computer Simulation; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D010406:Penicillins / Q000138:chemical synthesis* / Q000494:pharmacology; D013552:Swine
chemical_list: D000146:Acids, Carbocyclic; D050071:Bone Density Conservation Agents; D006023:Glycoproteins; D010406:Penicillins; D010397:Penicillanic Acid; C091137:purple acid phosphatase; D000135:Acid Phosphatase; C004408:aminopenicillanic acid