Staff profile

Dr Brian Smith FRACI CChem

Associate Professor, Principal Research Fellow

Faculty of Science, Technology and Engineering

School of Molecular Sciences
Department of Chemistry
La Trobe Institute for Molecular Science

Physical Sciences 3, Room 212, Melbourne (Bundoora)

 

Qualifications

BSc(Hons) PhD PGDMS

Membership of professional Associations

Fellow of the Royal Australian Chemical Institute, President of the Association of Molecualr Modellers of Australasia

Area of study

Biochemistry and Molecular Biology
Chemistry
Medicinal Chemistry

Brief Profile

 

I am an expert computational chemist and molecular modeller. I am skilled in the determination of protein structure by X-ray crystallography, in the analysis of protein structure, and in the design of protein mimetics and small-molecule inhibitors of protein function. I have authored over 110 papers in peer-reviewed journals, 2 book chapters and 3 invited reviews.

Following my PhD I took-up a postdoctoral position in Canberra to work with Prof Leo Radom, a world leader in the application of quantum mechanical methods. Here I studied the energetics and reactions of ionic species in the gas-phase, with particular emphasis in structural chemistry, thermochemistry, intermolecular processes and spectroscopy. Of particular note was my work on the accurate calculation of proton transfer reactions that led to many high-impact papers.

I returned to Melbourne in 1991 to join the Biomolecular Research Institute (BRI) as a research scientist. While at the BRI my research originally centred on computational studies of enzyme mechanism, particularly for Influenza virus neuraminidase, and the design of neuraminidase inhibitors. As part of these studies I solved the X-ray crystal structures of several neuraminidase-inhibitor complexes.

After the demise of the BRI in 2000 I moved to the Walter and Eliza Hall Institute (WEHI) as a founding member of the Structural Biology division. During the decade at WEHI my research interests centred on structural studies of proteins of the apoptosis machinery, particularly in identifying and developing compounds that modulate this process.

In July of 2101 I took up the position of LIMS Principle Research Fellow within the La Trobe Institute for Molecular Science.

I am a Fellow of the Royal Australian Chemical Institute (RACI), and life member of the World Association of Theoretical Chemists. I am the current president of the Association of Molecular Modellers of Australasia, and president of the Victoria Branch of the RACI.

Research interests

Anti-cancer drugs

- Agonists of apoptosis.

Anti-malarial therapeutics

- Studies of proteins in motility, protein export, and receptor binding.

Chemical structure and energetics

- Computational Chemistry and Molecular Modelling.

Neurodegenerative diseases

- Inhibitors of Alzheimer's BACE-1.

Organic, Pharmaceutical and Medicinal Chemistry

- Computer Assisted drug design.

Recent Publications

1.   P.E. Czabotar, E.F. Lee, M.F. van Delft, C.L. Day, B.J. Smith, D.C.S. Huang, W.D. Fairlie, M.G. Hinds and P.M. Colman. Structural insights into the degradation of Mcl-1 induced by BH3 domains. Proc. Nat. Acad. Sci. USA 104, 6217 (2007).

2.   E.F. Lee, P.E. Czabotar, B.J. Smith, K. Deshayes, K. Zobel, P.M. Colman and W.D. Fairlie. Crystal structure of ABT-737 complexed with Bcl-xL: implications for selectivity of antagonists of the Bcl-2 family. Cell Death Diff. 14, 1711 (2007).

3.   M.M. Zhang, B.R. Green, P. Catlin, B. Fielder, L. Azam, A. Chadwick, H. Terlau, J.R.McArthur, R.J. French, J. Gulyas, J.E. Rivier, B.J. Smith, R.S. Norton, B.M. Olivera, D. Yoshikami and G. Bulaj. Structure/function characterization of μ-conotoxin KIIIA, an analgesic, nearly irreversible blocker of neuronal mammalian sodium channels. J. Biol. Chem. 282, 30699 (2007).

4.   C. Beeton, B.J. Smith, J.K. Sabo, G. Crossley, D. Nugent, I. Khaytin, V. Chi, G. Chandy, M.W. Pennington and R.S. Norton. The D-diastereomer of ShK toxin selectively blocks voltage-gated K+ channels and inhibits T lymphocyte proliferation. J. Biol. Chem. 283, 988 (2008).

5.   J. Baum, C.J. Tonkin, A.S. Paul, M. Rug, B.J. Smith, S.B. Gould, D. Richard, T.D. Pollard and A.F. Cowman. A malaria parasite formin regulates actin polymerization and localizes to the parasite-erythrocyte moving junction during invasion. Cell Host Microbe 3, 188 (2008).

6.   A.N. Hodder, A.G. Maier, M. Rug, M. Brown, M. Mommel, M. Puig-de-Morales-Markinkovic, B. Smith, T. Triglia, J. Beeson and A.F. Cowman. Analysis of structure and function of the giant protein Pf332 in Plasmodium falciparum. Mol. Microbiol. 71, 48-65 (2009).

7.   K.K. Khoo, Z. Feng, B.J. Smith, M-M. Zhang, D. Yoshikami, B.M. Olivera, G. Bulaj and R.S. Norton. Structure of the analgesic μ-conotoxin KIIIA and effects on structure and function of disulfide deletion. Biochemistry 48, 1210 (2009).

8.   Y. Zhu, A. Davis B.J. Smith, J. Curtis and E. Handman. Leishmania major CorA-like magnesium transporters play a critical role in parasite development and virulence. Int. J. Paristol. 39, 713 (2009).

9.   A.G. Maier, J. Baum, B. Smith, D.J. Conway and A.F. Cowman. Polymorphisms in the erythrocyte binding antigens-140 and 181 affect function and binding but not receptor selectivity in Plasmodium falciparum. Infect. Immun. 77, 1689-1699 (2009).

10.   M.W. Pennington, C. Beeton, C.A Galea, B.J. Smith, V. Chi, K. Monaghan, A. Garcia, S. Rangaraju, A. Giuffrida, D. Plank, G. Crossley, D. Nugent, I. Khaytin, Y. LeFievre, I. Pechenko, C. Dixon, S. Chauhan, T. Inoue, X. Hu, R.V. Moore, R.S. Norton and K.G. Chandy. Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes. Mol. Pharmacol. 75, 762 (2009).

11.   E.F. Lee, J.D. Sadowsky, B.J. Smith, P.E. Czabotar, K.J. Peterson-Kaufman, P.M. Colman, S.H. Gellman and W.D. Fairlie. High-resolution structural characterization of a helical α/β-peptide foldamer bound to the anti-apoptotic protein Bcl-xL. Angew. Chem. Int. Ed. 48, 4318 (2009).

12.   T.F. de Konig-Ward, P.R. Gilson, J.A. Boddey, M. Rug, B.J. Smith, A.T. Papenfuss, P.R. Sanders, R.J. Lundie, A.G. Maier, A.F. Cowman, B.S. Crabb. A newly discovered protein export machine in malaria parasite. Nature 459, 945-949 (2009).

13.   H-K. Lee, M.D. Smith, B.J. Smith, J. Grussendorf, L. Xu, R.J. Gilles, H.S. White, G. Bulaj. Anticonvulsant Met-enkephalin analogs containing backbone spacers reveal alternative opioid signaling in the brain. ACS Chem. Biol. 4, 659-671 (2009).

14.   A.N. Hodder, R.L. Malby, O.B. Clarke, D.F. Fairlie, P.M. Colman, B.S. Crabb, B.J. Smith. Structural insights into the protease-like antigen Plasmodium falciparum SERA5 and its noncanonical active-site serine. J. Mol. Biol. 392, 154-165 (2009).

15.   E.F. Lee, P.E. Czabotar, H. Yang, B. Sleebs, G. Lessene, P.M. Colman, B.J. Smith, W.D. Fairlie. Conformational changes in Bcl-2 pro-survival proteins determine their capacity to bind ligands. J. Biol. Chem. 284, 30508-30517 (2009).

16.   G. Lessene, B.J. Smith, R. Gable, J. Baell. Characterisation of the two fundamental conformations of benzoylureas end elucidation of the factors that facilitate their conformational interchange. J. Org. Chem. 74, 6511-6525 (2009).

17.   K.M. Branson, H.D.T. Mertens, J.D. Swarbrick, J.I. Fletcher, L. Kedzierski, K.R. Gayler, P.R. Gooley, B.J. Smith. Discovery of inhibitors of Lupin Diadenosine 5′,5′′′-P1,P4-Tetraphosphate Hydrolase by virtual screening. Biochemistry 48, 7614-7620 (2009).

18.   A.E. Whitten, B.J. Smith, J.G. Menting, M.B. Margetts, N.M. McKern, G.O. Lovrecz, T.E. Adams, K. Richards, J.D. Bentley, J. Trewhella, C.W. Ward, M.C. Lawrence. Solution structure of ectodomains of the insulin receptor family: the ectodomain of the Type 1 insulin like growth factor receptor displays asymmetry of ligand binding accompanied by limited conformational change. J. Mol. Biol. 394, 878-892 (2009).

19.   B.J. Smith, K. Huang, G.K. Kong, S.J. Chan, S. Nakagawa, J.G. Menting, S.Q. Hu, J. Whittaker, D.F. Steiner, P.G. Katsoyannis, C.W. Ward, M.A. Weiss, M.C. Lawrence. Structural resolution of a tandem hormone-binding element in the insulin receptor and its implication for design of peptide agonists. Proc. Nat. Acad. Sci. USA 107, 6771-6776(2010).

20.   O.B. Clarke, A.T. Caputo, A. Hill, J. Vandenberg, B.J. Smith, J.M. Gulbis. Dual Gates Control the Ion Conduction Pathway of Potassium Channels. Cell 141, 1018-1029 (2010).

21.   P.J. Fuller, V. Yao, P.A. Komesaroff, B.J. Smith, M.C. Zennaro.Pseudohypoaldosteronism type 1: the index case revisited. Clin. Endo. 74, 408-410 (2011).

22.   B.E. Sleebs, P.E. Czabotar, W.J. Fairbrother, W.D. Fairlie, J.A. Flygare, D.C.S. Huang, W.J.A. Kersten, M.F.T. Koehler, G. Lessene, K. Lowes, J.P. Parisot, B.J. Smith, M.L. Smith, A.J. Souers, I.P. Street, H. Yang, J.B. Baell. Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma extra large (Bcl-xL) with potent pro-apoptotic cell-based activity. J. Med . Chem. 54, 1914-1926 (2011)

23.   E.F. Lee, G. Dewson, B.J. Smith, M. Evangelista, A. Pettikiriarachchi, C. Dogovski, M.A. Perugini, P.M. Colman, W.D. Fairlie. Crystal structure of a Bcl-w domain-swapped dimmer: implications for the function of Bcl-2 family proteins. Structure 19, 1467-1476 (2011).

24.   E.F. Lee, B.J. Smith, W.S. Horne, K.N. Mayer, M. Evangelista, P.M. Colman, S.H. Gellman, W.D. Fairlie. Structural basis of target recognition and selectivity for BH3-mimetic α/β-peptide foldamers generated via sequence-based design. ChemBioChem  12, 2025-2032 (2012).

25.   S. Dommaraju, C. Dogovski, P. Czabotar, L. Hor, B.J. Smith, M. Perugini. The catalytic mechanism and cofactor preference of dihydropicolinate reductase from methicillin-resistant Staphylococcus aureus. Arch. Biochem. Biophys. 512, 167-174 (2011).

26.   K. Natsuga, W. Nishie, B.J. Smith, S. Shinkuma, T.A. Smith, D.A.D. Parry, N. Oiso, K. Yoneda, M. Akiyama, H. Shimizu. Consequences of two different amino acid substitutions at the same codon in KRT14 indicate definitive roles of structural distortion in epidermolysis bullosa simplex pathogenesis. J. Invest. Derm. 131, 1869-1876 (2011).

27.   T. Nebl, H. Prieto, E. Kapp, B.J. Smith, C. Beckers, J.R. Yates, A.F. Cowman, C.J. Tonkin. Quantitative in vivo analyses reveal calcium-dependent phosphorylation sites and identifies a novel component of the Toxoplasma invasion motor complex. PLoS Pathogens. e10002222 (2011).

28.   K.K. Khoo, M.J. Wilson, B.J. Smith, M.M. Zhang, J. Gulyas, D. Yoshikami, J.E. Rivier, G. Bulaj, R.S. Norton. Lactam-stabilized helical analogues of the analgesic μ-conotoxin KIIIA. J. Med. Chem. 54, 7558-7566 (2011).

29.   M.D. Boersma, H.S. Haase, K.J. Peterson-Kaufman, E.F. Lee, O.B. Clarke, P.M. Colman, B.J. Smith, W.S. Horne, W.D. Fairlie, S.H. Gellman. Evaluation of diverse α/β backbone patterns for functional α-helix mimicry: Analogues of the Bim BH3 domain. J. Am. Chem. Soc. 134, 315-323 (2012).

30.   B.J. Smith. PS – a program for the analysis of helix geometry. J. Mol. Graphics Mod. 33, 52-60 (2012).

Older Publications

Click here for a full list of publications.

Research projects

Research Collaboration

  • Molecular modelling of α/β-foldamers and their interactions with regulators of apoptosis Collaborators: Prof Peter Colman, Dr Doug Fairlie and Dr Erinna Lee, The Walter and Eliza Hall Institute of Medical Research (WEHI)
  • Gating mechanisms in potassium channels Collaborator: Dr Jacqui Gulbis, WEHI
  • Modelling interactions of toxins with potassium channels Collaborator: Prof Ray Norton, Monash Institute of Pharmaceutical Sciences
  • Molecular modelling of insulin and IGF-1 binding to their receptors Collaborator: A/Prof Michael Lawrence, WEHI

Click here for a full description of research interests and current projects.

Current Research Projects

  • Plasmepsin-V (PMV).We have designed a series of inhibitors of PMV with sub-micromolar activity that we will now develop to improve affinity. These new molecules will be used to explore the function of this enzyme, and will serve as leads in the development of potential drug candidates.
  • Alzheimer’s disease. From an in silico screen of a library of commercially available compounds we identified 2 compounds that inhibit BACE-1 in vitro. We are actively engaged in the development of these compounds to improve affinity, selectivity and pharmacokinetic properties.

Research Grants

  • 2008 Designing and testing novel drug precursors for Alzheimer’s disease based on BACE1 inhibition. The JO and JR Wicking Trust. G. Evin, V. Kenche, B.J. Smith.
  • 2009-11 The molecular basis of cell transformation produced by TPD52 overexpression. NSW Cancer Council. J.A. Byrne, R.K. Bright, D.R. Catchpoole, B.J. Smith.
  • 2010-12 Novel compounds to disrupt protein-protein interactions. ARC Discovery Grant. P.M. Colman, B.J. Smith, W.D. Fairlie.
  • 2010-12 Evolution of a protein fold from toxin to physiological regulator: an endogenous potassium channel blocker in humans. ARC Discovery Grant. R.S. Norton, B.J. Smith, G.K. Chandy, M.W. Pennington.
  • 2011-13 Function and inhibition of plasmepsin V in targeting malaria virulence proteins into human erythrocytes. NHMRC Project Grant. J. Boddey, A.N. Hodder, B.J. Smith.
  • 2012-14 Development of small molecule modulators of apoptosis. NHMRC Project Grant. G. Lessene, P. Czabotar, D. Segal, I. Street, B.J. Smith.