Staff profile

Dr Brian Smith FRACI CChem

Associate Professor, Principal Research Fellow, Deputy Head of School

Faculty of Science, Technology and Engineering
School of Molecular Sciences
Department of Chemistry
La Trobe Institute for Molecular Science

LIMS1, Room 503, 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

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 120 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.     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).

2.  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).

3.  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). Cover illustration.

4.  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).

5.  O.B. Clarke, A.T. Caputo, A. Hill, J. Vandenberg, B.J. Smith, J.M. Gulbis. Domain reorientation and rotation of an intracellular assembly regulates conduction in Kir Potassium Channels. Cell 141, 1018-1029 (2010).

6.  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).

7.  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).

8  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 dimer: implications for the function of Bcl-2 family proteins. Structure 19, 1467-1476 (2011). 

9.  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).

10. K. Natsuga, W. Nishie, B.J. Smith, S. Shinkuma, T.A. Smith, D.A.D. Parry, N. Oiso, A. Kawada, 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)

11. T. Nebl, J.H. Prieto, E. Kapp, B.J. Smith, M.J. Williams, 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, 7, e10002222 (2011).

12.  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 Bcl-xL recognition by a BH3-mimetic a/b-peptide generated by sequence-based design. ChemBioChem 12, 2025-2032 (2011) *Equal first author. Cover illustration.

13. 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 m-conotoxin KIIIA. J. Med. Chem. 54, 7558-7566 (2011).

14. 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 a/b backbone patterns for functional a-helix mimicry: Analogues of the Bim BH3 domain. J. Am. Chem. Soc. 134, 315-323 (2012).

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

16.  A.N. Hodder, P.E. Czabotar, A.D. Uboldi, O.B. Clarke, C.S. Lin, J. Healer, B.J. Smith, A.F. Cowman. Insights into Duffy Binding-like domains through the crystal structure and function of the merozoite surface protein MSPDBL2 from Plasmodium falciparum. J. Biol. Chem. 287, 32922-32939 (2012).

17. H.M. Nguyen, H. Miyazaki, N. Hoshi, B.J. Smith, N. Nukina, A.L. Goldin, K.G. Chandy. A Modulation of voltage-gated K+ channels by the sodium channel β1 subunit. Proc. Nat. Acad. Sci. USA 109, 18577-18582 (2012). Faculty 1000 citation.

18.  T.P. Pell, S.A. Couchman, S. Ibrahim, D.J.D. Wilson, B.J. Smith, P.J. Barnard, J.L. Dutton. Diverse reactions of PhI(OTf)2 with common 2-electron ligands: Complex formation, oxidation and oxidative coupling. Inorg. Chem. 51, 13034-13040 (2012).

19.  T. Okamoto, K. Zobel, B.J. Smith*, A. Fedorova, C. Quan, H. Yang, P.M. Colman, W.J. Fairbrother, D.C.S. Huang, K. Deshayes, P.E. Czabotar. Stabilizing the helical BimBH3 peptide does not enhance binding affinity or biological activity. ACS Chem. Biol. 8, 297-302 (2013). *Corresponding co-author.

20.  J.G. Menting, J Whittaker, M.B. Margetts, L.J.Whitaker, G.K.W. Kong, B.J. Smith, C.J. Watson, L. Zakova, E. Kletvikpva, J. Jiracek, D.F. Steiner, S.J. Chan, G.G. Dodson, A.M. Brzozowski, M.A. Weiss, C.W. Ward, M.C. Lawrence. How insulin engages its primary site on the insulin receptor. Nature. 493, 241-245 (2013).

21.  P.E. Czabotar, D. Westphal, G. Dewson, S. Ma, C. Hockings, W.D. Fairlie, E.F Lee, S. Yao, A.Y. Robin, B.J. Smith, D.C.S. Huang, R.M. Kluck, J.M. Adams, P.M. Colman. Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerisation to induce apoptosis. Cell. 152, 519-531 (2013).

22.  H. Nguyen, C.A. Galea, B.J. Smith, R.S. Norton, K.G. Chandy. Intracellular trafficking of the Kv1.3 potassium channel is regulated by the pro-domain of a matrix metalloprotease. J. Biol. Chem. 288, 6451-6464 (2013).

23.  G. Lessene, P.E. Czabotar, B.E. Sleebs, K. Zobel, K.L. Lowes, J.M. Adams, J.B. Baell, P.M. Colman, K. Deshayes, W.J. Fairbrother, J.A. Flygare, P. Gibbons, W.J.A. Kersten, S. Kulasegaram, R.M. Moss, J.P. Parisot, B.J. Smith, J.P. Street, H. Yang, D.C.S. Huang, K.G. Watson. Structure-guided design of a selective BCL-XL inhibitor. Nat. Chem. Biol. 9, 390-397 (2013).

24. B.J. Smith*, E.F. Lee, J.W. Checco, M. Evangelista, S.H. Gellman, W.D. Fairlie. Structure-guided rational design of a/b-peptide foldamers with high affinity for Bcl-2 family pro-survival proteins. ChemBioChem 14, 1564-1572 (2013). *Corresponding co-author.

25. C.Y. Leow, C. Willis, A. Osman, L. Mason, A. Simon, R. Gasser, B.J. Smith, M.K. Jones, A. Hofmann. Crystal structure and immunological properties of the first annexin from Schistosoma mansoni  - Insights into the structural integrity of the schistosomal tegument. FEBS J. 281, 1209-1225 (2014).

26.  T. Okamoto, K. Zobel, B.J. Smith*, A. Fedorova, C. Quan, H. Yang, P.M. Colman, W.J. Fairbrother, D.C.S. Huang, K. Deshayes, P.E. Czabotar. Further insights into the effects of pre-organizing the BimBH3 helix. (In press). *Corresponding co-author.

27. R.M. Brady, A. Vom, M.J. Roy, N. Toovey, B.J. Smith, R.M. Moss, E. Hazis, D.C.S. Huang, J.P. Parisot, H. Yang, I.P. Street, P.M. Colman, P.E. Czabotar, J.B. Baell, G. Lessene. De-Novo Designed Library of Benzoylureas as Inhibitors of BCL-XL: Synthesis, Structural and Biochemical Characterization. J. Med. Chem. 57, 1323-1343 (2014).

28. H. Shahheydari, S. Frost, B.J. Smith, G.E. Groblewski, Y. Chen, J.A. Byrne. Identification of PLP2 and RAB5C as novel TPD52 binding partners through yeast two-hybrid screening. Mol. Biol. Rep. (In press).

29. M.F.T. Koehler, P. Bergeron, E.F. Choo, K. Lau, C. Ndubaku, D. Dudley, B.E. Sleebs, C.S. Rye, G. Nikolakopoulos, C. Bui, S. Kulasegaram, W.J.A. Kersten, B.J. Smith, P.E. Czabotar, P.M. Colman, D.C.S. Huang, J.B. Baell, K.G. Watson, L. Hasvold, Z-F. Tao, L. Wang, A.J. Souers, S.W. Elmore, J.A. Flygare, W.J. Fairbrother, G. Lessene. Structure-guided rescaffolding of selective antagonists of BCL-XL. ACS Med. Chem. Lett. (In press).

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.

•    2013-15 Functional analysis of the Toxoplasma Myosin driving tissue dissemination and host cell invasion. NHMRC Project Grant. G. Lessene, P. Czabotar, D. Segal, I. Street, B.J. Smith.

•    2013-15 BioPPSy: An open source BIOchemical Property Prediction SYstem. ARC Discovery Project. B.J. Smith.

•    2014-16 Targeting the insulin and insulin-like growth factor receptors in cancer, diabetes and Alzheimer’s disease. NHMRC Project Grant. M. Lawrence, M. Weiss, B.J. Smith, C. Ward.