The Medicinal Chemistry Group
The Walter and Eliza Hall Institute Medicinal Chemistry Group, led by Associate Professor Jonathan Baell, Dr Guillaume Lessene and Dr Keith Watson, conducts research aimed at developing new therapeutically useful molecules. Combining synthetic organic chemistry with a knowledge of structural biology and principles of drug design, we focus on small molecules and their biological applications.
Projects in the laboratory currently focus on cancer and parasitic diseases such as malaria, human African trypanosomiasis, leishmaniasis and Chagas’ disease. Within some of these areas - such as cancer - there are several projects, which have grown from different origins, both in terms of the source of the initial hit molecule and the target with which it is interacting.
Approaches to finding hit molecules
Within the lab, our target molecules are derived from one of three approaches: (i) structure-based design; (ii) natural products with known activity; and (iii) high throughput chemical screening. Once a hit is identified and validated, we adopt standard medicinal chemistry techniques such as structure-activity relationships in the quest to enhance the potency and improve the properties of the chosen molecules with the ultimate aim of producing a drug that can enter clinical trials.
(i) Structure-based drug design
Advances in structural biology have given chemists the power to rationally design drug-like molecules that, theoretically, will bind to a specific receptor or protein of interest. In the area of peptidomimetics, molecular modeling enables the selection of a backbone scaffold, which will project the residue mimics in the necessary direction in space. Beyond converting these calculations into the chemical reality of a biologically active hit, we aim to optimise the potency and selectivity of our molecules through structure-activity relationships. In some instances, thorough conformational studies are used to determine whether the molecules in fact adopt the designed shape.
(ii) Natural products and their derivatives
Molecules found in nature have evolved over billions of years to meet the needs of the plant or organism that produces it. Typically, this involves interaction with proteins or enzymes within a biological system. It follows that these molecules, while adapted to use in its original environment, might find similar interactions inside the human body. We are interested in natural products that have been reported to have promising biological activity, such that we can then work towards enhancing this activity in the search for therapeutic utility.
(iii) High-throughput chemical screening (HTCS)
With a library of over 100,000 commercially available synthetic compounds - and soon to be expanded towards 200,000 compounds, our colleagues in the HTCS group are able to rapidly test ‘lead-like’ molecules against many biological targets. Selected hits from a variety of assays are then used to initiate synthetic chemistry programs.
The Lab
Major equipment
NMR - Bruker Avance II, 300 MHz
HPLC - Waters Alliance HT 2795
LCMS - Finnigan LCQ Advantage MAX
Prep-LCMS - Waters
Infrared - Bruker Tensor27 FT-IR
Automated Flash Chromatography System - Biotage FlashMaster II
Microwave - CEM Discover Lab Mate
MBRAUN Solvent Purification System
Collaborations
Our chemists work closely with world-leading biologists and biochemists, both internal and external, creating a dynamic environment of drug discovery.
Internal divisions
Other Institutions
The University of Melbourne
La Trobe University
The Ludwig Institute for Cancer Research
The Howard Florey Institute
The CRC for Cancer Therapeutics
Private collaborations
Genentech Inc
Abbott Laboratories
Bionomics Ltd
Murigen
DNDi