SEMINAR: School of Chemistry and Biochemistry Seminar
|School of Chemistry and Biochemistry Seminar : A Tale of Two Metalloenzymes:
Binuclear metallohydrolases are a functionally diverse class of metalloenzyme whose members require two closely spaced metal ions in their active site to catalyse the hydrolysis of amides and phosphate esters .
Purple acid phosphatases (PAPs) are found in animals, plants and fungi. They catalyse the hydrolysis of a broad range of phosphate esters and anhydrides under acidic conditions. PAPs contain an Fe(III) and a divalent metal ion in their active site. In animals, they are responsible for bone resorption in osteoclasts, and there is substantial evidence to support the role of PAPs in osteoporosis, a disease characterised by excessive bone resorption. PAP is, therefore, an attractive target for the development of drugs to treat this debilitating condition .
β-Lactam-containing antibiotics such as penicillins, cephalosporins and carbapenems, are the most widely used drugs for the treatment of bacterial infections. A large number of pathogenic bacteria are now producing metallo-β-lactamases (MBLs), enzymes that hydrolyse the β-lactam rings of nearly all known classes of β-lactam-containing antibiotics, and so make these bacteria resistant to these drugs. MBLs contain two zinc(II) ions in their active sites. As yet, there are no clinically useful antagonists of MBLs, and so bacteria expressing these enzymes pose a significant risk to human health.
This presentation will describe a multidisciplinary approach to the development of drug leads against PAP and MBL. Our approaches to the development of enzyme inhibitors have been twofold. In the first approach we have use the crystal structures of PAPs and MBLs to rationally design ligands to bind to the binuclear metal centre of the active sites, and to maximise non-covalent interactions at locations proximal to the active site [2,3]. In the second approach we have used fragment-based screening to identify small molecule inhibitors of PAP, and we have obtained crystals structures of these complexed in the active site of the enzyme . These studies have led to development of the most potent PAP inhibitors yet reported.
 Schenk, Mitic, Gahan, Ollis, McGeary & Guddat, Acc. Chem. Res., 2012, 45, 1593.
 Mohd-Pahmi, Hussein, Schenk & McGeary, Bioorg. & Med. Chem. Lett., 2011, 21, 3092.
 Faridoon, Hussein, Vella, Ul Islam, Ollis, Schenk & McGeary, Bioorg. & Med. Chem. Lett., 2012, 22, 380.
 Feder, Hussein, Clayton, Kan, Schenk, McGeary & Guddat, Chem. Biol. & Drug Des., 2012, In Press. doi: 10.1111/cbdd.12001
Associate Professor Ross McGeary
Bayliss Building Lecture Theatre G33
Wed, 03 Oct 2012 12:00
Wed, 03 Oct 2012 13:00
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Wed, 03 Oct 2012 10:04
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