Martin L. Williams

Monash University (Australia) · Monash Institute of Pharmaceutical Sciences

Disulfide bond protein A (DsbA) is an oxidoreductase enzyme that catalyzes the formation of disulfide bonds in Gram-negative bacteria. In Escherichia coli, DsbA (EcDsbA) is essential for bacterial virulence, thus inhibitors have the potential to act as antivirulence agents. A fragment-based screen was conducted against EcDsbA and herein we describe...

DsbA enzymes catalyze oxidative folding of proteins that are secreted into the periplasm of Gram-negative bacteria, and they are indispensable for the virulence of human pathogens such as Vibrio cholerae and Escherichia coli . Therefore, targeting DsbA represents an attractive approach to control bacterial virulence. X-ray crystal structures reveal...

DsbA enzymes catalyze oxidative folding of proteins that are secreted into the periplasm of Gram-negative bacteria, and they are indispensable for the virulence of human pathogens such as Vibrio cholerae and Escherichia coli. Therefore, targeting DsbA represents an attractive approach to control bacterial virulence. X-ray crystal structures reveal...

DsbA enzymes catalyze oxidative folding of proteins that are secreted into the periplasm of Gram-negative bacteria, and they are indispensable for the virulence of human pathogens such as Vibrio cholerae and Escherichia coli. Therefore, targeting DsbA represents an attractive approach to control bacterial virulence. X-ray crystal structures reveal...

The presence of suitable cavities or pockets on protein structures is a general criterion for a therapeutic target protein to be classified as ‘druggable’. Many disease-related proteins that function solely through protein–protein interactions lack such pockets, making development of inhibitors by traditional small-molecule structure-based design m...

A bottleneck in fragment-based lead development is the lack of systematic approaches to elaborate the initial fragment hits, which usually bind with low affinity to their target. Herein we describe analysis using X-ray crystallography of a diverse library of compounds prepared using microscale parallel synthesis. This approach yielded an 8-fold inc...

Peroxisome proliferator-activated receptor α (PPARα) is a transcriptional regulator of lipid metabolism. GW7647 is a potent PPARα agonist that must reach the nucleus to activate this receptor. In cells expressing human fatty acid–binding protein 1 (FABP1), GW7647 treatment increases FABP1’s nuclear localization, and potentiates GW7647-mediated PPAR...

The worldwide incidence of neisserial infections, particularly gonococcal infections, is increasingly associated with antibiotic resistant strains. In particular, extensively drug-resistant Neisseria gonorrhoeae strains that are resistant to third-generation cephalosporins are a major public health concern. There is a pressing clinical need to iden...

International research is increasingly demonstrating that psychedelic-assisted psychotherapy can enhance psychotherapeutic outcomes and be effective for some treatment-refractory mental illnesses; however, there is an absence of any such research in Australia. A review of psychedelic science has been conducted with a focus on psychedelic-assisted p...

DsbD is a disulfide bond reductase present in the inner membrane of many Gamma-Proteobacteria. In the human pathogen Neisseria meningitidis, DsbD is required for viability and represents a potential target for the development of antibiotics. Here we report the chemical shift assignments (H(N), N, C(α) and C(β)) for the reduced and oxidized forms of...

We describe a general approach to determine the binding pose of small molecules in weakly bound protein-ligand complexes by deriving distance constraints between the ligand and methyl groups from all methyl-containing residues of the protein. We demonstrate that using a single sample, which can be prepared without the use of expensive precursors, i...

http://onlinelibrary.wiley.com/doi/10.1002/anie.201410341/full Adams, L. A.‡, Sharma, P‡., Mohanty, B., Ilyichova, O. V., Mulcair, M. D., Williams, M. L., Gleeson, E. C., Totsika, M., Doak, B. C., Caria, S., Rimmer, K., Horne, J., Shouldice, S. R., Vazirani, M., Headey, S. J., Plumb, B. R., Martin, J. L., Heras, B., Simpson, J. S. and Scanlon, M....

The aqueous cytoplasm of cells poses a potentially significant barrier for many lipophilic drugs to reach their sites of action. Fatty acid binding proteins (FABPs) bind to poorly water-soluble fatty acids (FAs) and lipophilic compounds and facilitate their intracellular transport. Several structures of FA in complex with FABPs have been described,...

The function and dynamics of the thiol-disulfide oxidoreductase DsbA in the low-GC gram positive bacterium, Staphylococcus aureus, are yet to be elucidated. Here we report 13C, 15N and 1H assignments for the oxidised and reduced forms of SaDsbA as a prelude to further studies on the enzyme.

An unusual type of π-electron delocalization in Y-shaped molecules related to guanidine and its protonated form, the guanidinium ion, has been studied by ab initio methods at the STO-3G and 3-21G levels. Results are reported for tautomeric, rotameric, and protonated forms of the oxygen-substituted guanidine series (urea, carbamic, and carbonic acid...