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Dr John Deadman
Head Of Medicinal Chemistry
Amrad Operations Pty.Ltd.
576 Swan Street Richmond, Victoria 3121
Email: jdeadman@amrad.com.au
Tel: +61-3-9208 4212
Fax: +61-3-9208 4100
Homepage:
| Research |
My research has been based on the premise that proteases and proteinases were valid targets for discovery of therapeutics, but we could never decide on which word we preferred.
Study of proteolytic enzymes involved in activation and feedback systems such as the coagulation cascade highlighted as the basis of design the significance of specificity for the target enzyme amongst homologues. Serial medicnal chemistry approaches lead to a reversible, transition state (TS) amino-boronate thrombin inhibitor, which is in clinical development (1,2). In another approach selectivity could be achieved with a TS-inhibitor by attaching peptide sequences. To do this we developed the chemistry for solid phase synthesis of amino-bornates.(3)
The mechanism of TS isosteres was investigated, with the collaboration of protein structure groups. For example a dipeptide-aminophosphonate inhibitor was sproven to work through the first penta-co-ordinate complex of a phosphorous atom stabilized by the catalytic site of a protease (brookhaven code ) (4).
Speculating wildly we considered that this was the hydrolytic water (of the enzyme de-acylation step) trapped by the heteroatom.
Application of computational chemistry to structure based drug design allowed us to consider targeting of proteinases that display considerable allosteric movement or flexibility in ligand binding.(5)
While my current focus is on other drug ligand interactions, we are grateful for the continued work of our former colleagues to complete some studies. I remain optimistsic that protease will arise as a target again.
Current Areas of research where collaboration would be of interest:
Anti-viral and anti-infective agents and cytokine mediated disease (Asthma, inflammtory disease etc).
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| Collaborations |
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| Publications |
1)Deadman, J.J., Elgendy, S.; Goodwin, C.A.; Green,D.; Skordalakes, E.; Patel, G.; Baban, J.A.; Claeson, G; Kakkar,V.V.; Scully, M.F. Characterisation of Neutral P1 Peptide Boronates as a New Class of Thrombin Inhibitor, J.Med.Chem., 1995, 38, 1511-1522.
2) Skordalakes, E.; Tyrell, R.; Elgendy, S.; Goodwin, C.A.; Green, D.; Dodson, G.; Scully, M.F.; Freyssinet, J.-M.H.; Kakkar, V.V. and Deadman, J.J. Crystallographic Structures of Human a-Thrombin Complexed to Peptide Boronic Acids Lacking a Positive Charge at P1. Evidence of Novel Interactions. J.Am.Chem.Soc. 1997, 119, 9935-9936.
3) Skordalakes, E.; Elgendy, S.; Goodwin, C.A.; Green, D.; Scully, M.F.; Kakkar, V.V. Dodson, G.; Freyssinet, J.-M.; and Deadman, J.J. Bifunctional Peptide Boronate Inhibitors of Thrombin: Crystallographic Analysis of Inhibition Enhanced by linkage to an Exosite 1 Binding Peptide. Biochemistry, 1998, 37, 14420-14427
4) Skordalakes, E.; Green, D.; Dodson, G.G; Hudson, H., Goodwin, C.A; Scully, M.F.; Kakkar, V.V. and Deadman, JJ. 'Inhibition of Human a-Thrombin by a Phosphonate Tripeptide Proceeds via a Metastable Pentacoordinated Phosphorus Intermediate' J.Mol.Biol., 2001. 311, 549-555
5) Greenidge PA, Merette SA, Beck R, Dodson G, Goodwin CA, Scully MF, Spencer J, Weiser J, Deadman JJ. 'Generation of ligand conformations in continuum solvent consistent with protein active site topology: application to thrombin' J Med Chem. 2003, 46, 1293-305
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