My fields of research are structural biology and rational drug design. The group uses X-ray crystallography and other physical measurements to determine how structure influences the function of enzymes. This knowledge allows us to rationally design and develop enzyme inhibitors that can act as therapeutic agents or herbicides. Four enzyme classes are being studied:
(i) those involved in nucleotide biosynthesis;
(ii) enzymes in the branched-chain amino acid biosynthesis pathway;
(iii) metalloenzymes and;
(iv) serine proteases in the blood clotting cascade.
Hypoxanthine-guanine phosphoribosyltransferase takes the naturally 6-oxopurines, hypoxanthine or guanine and phosphoribosylpyrophosphate and converts these to the nucleotides required for DNA/RNA synthesis. We are now targeting the Plasmodium falciparum and Plasmodium vivax enzymes to discover new inhibitors that we design to test as anti-malarial drugs.
We determined the three-dimesional structures of the catalytic subunit of plant, bacterial and fungal acetohydroxyacid acid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthetic pathway. In plants, this enzyme is the target for a number of commercial herbicides including members of the sulfonylurea and imidazolinone families. Two goals are:
(i) to use this data to discover new AHAS inhibitors as biocide leads and;
(ii) to determine the structure of the regulatory subunit of AHAS.
We have determined the structures of plant, and bacterial ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid biosynthetic pathway. The enzyme contains two closely spaced metals and NADPH and undergoes major structural changes during its catalytic cycle. We are currently investigating these structures. KARI’s position in the branched-chain biosynthesis pathway also makes it an attractive target to discover new biocides.
We have determined the structures of plant and animal purple acid phosphatase, a metalloenzyme with two closely spaced metal centres. Based on our latest structures we have proposed a detail mechanism of catalysis for this enzyme. Inhibitors of the animal enzyme are considered excellent anti-osteoporotic drug leads.
We are studying the structure and inhibition of the serine proteases, plasmin and plasma kallikrein, and their roles in the blood clotting cascade. Our group is discovering protease inhibitors within Australian snake venoms as potential therapeutic drug leads.