Associate Professor Mark Smythe

Principal Research Fellow - GL

Institute for Molecular Bioscience
+61 7 334 62977


Research Interests

  • Combinatorial Chemistry and Molecular Design
    The approach is to combine protein structural information with combinatorial chemistry, resulting in the design and synthesis of molecules that mimic protein structure, ultimately leading to the discovery of compounds that mimic protein function. We are actively pursuing small molecules for cytokine and G-protein coupled receptors.
  • Protein-protein interactions
    Many biological processes are carried out, or regulated, through protein-protein interactions. Despite their physiological significance, they remain one of the most difficult molecular recognition events to inhibit or mimic. We have developed molecular design processes that successfully identify small molecular candidates which modulate the function of protein-protein interactions. We currently have several lead molecules against numerous protein-protein interaction targets.
  • Molecular design
    We have developed an integrated design platform for library design and structure-based design of molecules that modulate protein-protein interactions. This approach includes a set of unique biological descriptors for library design, a purpose-built virtual screening of virtual library platform and databases comprising large virtual libraries of compounds. Using these methodologies we design and synthesise arrays of molecules that sample biologically relevant diversity space for primary screening, as well as arrays of molecules specifically targetted for a therapeutic protein of interest.
  • Combinatorial chemistry
    Current strategies in library design involve the calculation of hundreds of potential descriptors that define various chemical characteristics, and selecting a diverse set of compounds in this descriptor space. With hundreds of available descriptors it is difficult to know which descriptors, if any, are important or essential for describing biological activity. Consequently such procedures result in the optimisation of libraries in chemical descriptor space, which has little impact on biologically relevant regions of that space. To overcome this we have developed a series of biologically-relevant descriptors that are used in library design. As a consequence, we aim to identify the biologically-relevant structural regions of chemical diversity and design and synthesise arrays of molecules that match this diversity space. We have developed new linkers and auxiliaries to aid combinatorial synthesis and a molecular design platform to achieve these objectives. We have synthesised various constrained cyclic peptide libraries (molecular toolkit libraries) and libraries of macrocycles and heterocycles. We have a particular focus on the discovery and exploitation of privileged structures.


  • Doctor of Philosophy, University of Melbourne
  • Bachelor (Honours) of Science (Advanced), James Cook University
  • Bachelor of Science, James Cook University


  • Redd, Meredith A, Yoshikawa, Yusuke, Khan, Nemat, Waqar, Maleeha, Saez, Natalie J, Outhwaite, Jennifer E, Russell, Jake S, Hanna, Amy D, Chiu, Han S, Er, Sing Yan, Butcher, Neville J, Mardon, Karine, Fraser, John F, Smythe, Mark L, Rash, Lachlan D, Thomas, Walter G, King, Glenn F, Reichelt, Melissa E and Palpant, Nathan J (2024). Acid-sensing ion channel 1a blockade reduces myocardial injury in rodent models of myocardial infarction. European Heart Journal, 45 (17), 1571-1574. doi: 10.1093/eurheartj/ehad793

  • Yarlagadda, Sai, Kulis, Christina, Noakes, Peter G. and Smythe, Mark L. (2021). Hematopoietic prostaglandin D synthase inhibitor PK007 decreases muscle necrosis in DMD mdx model mice. Life, 11 (9) 994, 994. doi: 10.3390/life11090994

  • Werder, Rhiannon B., Lynch, Jason P., Simpson, Jennifer C., Zhang, Vivian, Hodge, Nick H., Poh, Matthew, Forbes-Blom, Elizabeth, Kulis, Christina, Smythe, Mark L., Upham, John W., Spann, Kirsten, Everard, Mark L. and Phipps, Simon (2018). PGD2/DP2 receptor activation promotes severe viral bronchiolitis by suppressing IFN-λ production. Science Translational Medicine, 10 (440) eaao0052, eaao0052. doi: 10.1126/scitranslmed.aao0052

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  • Doctor Philosophy

  • Doctor Philosophy

  • (2012) Doctor Philosophy

View all Supervision


Book Chapter

  • Bourne, Gregory T., Nielson, Jonathon L., Coughlan, Justin F., Darwen, Paul, Campitelli, Marc R., Horton, Douglas A., Rhumann, Andreas, Love, Stephen G., Tran, Tran T. and Smythe, Mark L. (2005). A convenient method for the synthesis of cyclic peptide libraries. Peptide synthesis and applications. (pp. 151-166) edited by John Howl. Clifton, NJ, USA: Humana Press.

Journal Article

Conference Publication

Grants (Administered at UQ)

PhD and MPhil Supervision

Current Supervision

Completed Supervision

  • (2012) Doctor Philosophy — Principal Advisor

  • (2008) Doctor Philosophy — Principal Advisor

  • (2005) Doctor Philosophy — Principal Advisor

  • (2007) Doctor Philosophy — Associate Advisor

  • (2004) Doctor Philosophy — Associate Advisor