A5039451111- Chemical Synthesis and Analysis
- RNA and protein synthesis mechanisms
- Community Development and Social Impact
- DNA and Nucleic Acid Chemistry
- DNA Repair Mechanisms
- Biochemical and Molecular Research
- Machine Learning in Bioinformatics
- Genomics and Chromatin Dynamics
- Computational Drug Discovery Methods
- RNA modifications and cancer
- Protein Structure and Dynamics
- Neurological diseases and metabolism
- Viral-associated cancers and disorders
- CRISPR and Genetic Engineering
- Ubiquitin and proteasome pathways
- Microtubule and mitosis dynamics
- PARP inhibition in cancer therapy
- Radioactive element chemistry and processing
- Cellular transport and secretion
- Lymphoma Diagnosis and Treatment
- Chemical Synthesis and Characterization
- 3D Printing in Biomedical Research
- Chemical Reactions and Isotopes
- Cancer-related Molecular Pathways
- Analytical Chemistry and Chromatography
University of Cambridge
2010-2024
Launceston General Hospital
2012
University of Miami
2000-2001
University of Manchester
1974
A microfluidic device capable of storing picoliter droplets containing single bacteria at constant volumes has been fabricated in PDMS. Once captured that remain static the device, express both a red fluorescent protein (mRFP1) and enzyme, alkaline phosphatase (AP), from biscistronic construct. By measuring fluorescence intensity mRFP1 inside cells product formed as result enzymatic activity outside cells, gene expression can be simultaneously continuously monitored. collecting data many...
Abstract The ability to identify inhibitors of protein–protein interactions represents a major challenge in modern drug discovery and the development tools for chemical biology. In recent years, fragment‐based approaches have emerged as new methodology discovery; however, few examples small molecules that are active against chemotherapeutic targets been published. Herein, we describe approach targeting interaction between tumour suppressor BRCA2 recombination enzyme RAD51; it makes use...
Bifunctional molecules known as PROTACs simultaneously bind an E3 ligase and a protein of interest to direct ubiquitination clearance that protein, they have emerged in the past decade exciting new paradigm drug discovery. In order investigate permeability properties these large molecules, we synthesized two panels PROTAC constructed from range protein-target ligands, linkers, ligands. The androgen receptor, which is well-studied field was used model system. physicochemical are discussed.
BRCA2 controls RAD51 recombinase during homologous DNA recombination (HDR) through eight evolutionarily conserved BRC repeats, which individually engage via the motif Phe-x-x-Ala. Using structure-guided molecular design, templated on a monomeric thermostable chimera between human and archaeal RadA, we identify CAM833, 529 Da orthosteric inhibitor of RAD51:BRC with Kd 366 nM. The quinoline CAM833 occupies hotspot, Phe-binding pocket methyl substituted α-methylbenzyl group Ala-binding pocket....
Aurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization enzymatic activity of are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery develop small molecule inhibitors A-TPX2 protein-protein (PPI). Our compound,
Get stuck in: Pantothenate synthetase is an attractive target for the development of novel small-molecule drugs against Mycobacterium tuberculosis. Three related sulfamoyl adenylate inhibitors were designed to closely mimic structure reaction intermediate, pantoyl adenylate. The most potent inhibitor exhibited dissociation and inhibition constants about 100 nM. structural elucidation compounds bound enzyme will aid subsequent inhibitors. Detailed facts importance specialist readers are...
A new strategy that combines the concepts of fragment-based drug design and dynamic combinatorial chemistry (DCC) for targeting adenosine recognition sites on enzymes is reported. We demonstrate use 5'-deoxy-5'-thioadenosine as a noncovalent anchor fragment in libraries templated by Mycobacterium tuberculosis pantothenate synthetase. benzyl disulfide derivative was identified upon library analysis HPLC. Structural binding studies protein-ligand complexes X-ray crystallography isothermal...
Abstract The development of small molecules that inhibit protein–protein interactions continues to be a challenge in chemical biology and drug discovery. Herein we report the indole‐based fragments bind shallow surface pocket humanised surrogate RAD51. RAD51 is an ATP‐dependent recombinase plays key role repair double‐strand DNA breaks. It both self‐associates, forming filament structures with DNA, interacts BRCA2 protein through common “FxxA” tetrapeptide motif. We elaborated previously...
Abstract False-positives plague High Throughput Screening in general and are costly as they consume resource time to resolve. Methods that can rapidly identify such compounds at the initial screen therefore of great value. Advances mass spectrometry have led ability inhibitors drug discovery applications by direct detection an enzyme reaction product. The technique is free from some artefacts trouble classical assays fluorescence interference. Its nature negates need for coupling enzymes...
Multicentric Castleman's disease (MCD) is a lymphoproliferative disorder that can be defined based upon both clinical and pathological characteristics. The features of this frequently fatal include fever, generalized lymphadenopathy, fatigue, splenomegaly, hepatomegaly, pancytopenia. Recently, severe forms have been diagnosed in HIV positive patients. Human herpesvirus type 8 (HHV-8) DNA sequences detected peripheral blood mononuclear cells (PBMCs) patients with Kaposi's sarcoma MCD,...
Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are emerging as attractive therapeutic targets in diseases, such cancer, immunological disorders, and neurodegeneration, owing to their central role regulating cell signaling pathways that either dysfunctional or can be modulated promote survival. Different modes of binding may enhance inhibitor selectivity reduce off-target effects cells. Here, we describe efforts improve the physicochemical properties selective PI5P4Kγ inhibitor,...
Protein-protein interactions (PPIs) are increasingly important targets for drug discovery. Efficient fragment-based discovery approaches to tackle PPIs often stymied by difficulties in the production of stable, unliganded target proteins. Here, we report an approach that exploits protein engineering "humanise" thermophilic archeal surrogate proteins as small-molecule inhibitor and exemplify this development inhibitors against PPI between recombinase RAD51 tumour suppressor BRCA2. As human...
Owing to their central role in regulating cell signaling pathways, the phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are attractive therapeutic targets diseases such as cancer, neurodegeneration, and immunological disorders. Until now, tool molecules for these kinases have been either limited potency or isoform selectivity, which has hampered further investigation of biology drug development. Herein we describe virtual screening workflow identified a series thienylpyrimidines...
Homologous recombination is essential for repair of DNA double-strand breaks. Central to this process a family recombinases, including archeal RadA and human RAD51, which form nucleoprotein filaments on damaged single-stranded ends facilitate their ATP-dependent repair. ATP binding hydrolysis are dependent the formation filament comprising RadA/RAD51 DNA, with bound between adjacent protomers. We demonstrate that truncated, monomeric Pyrococcus furiosus monomerised RAD51 retain ability bind...
Multicentric Castleman's disease (MCD) is a lymphoproliferative disorder that can be defined based upon both clinical and pathological characteristics. The features of this frequently fatal include fever, generalized lymphadenopathy, fatigue, splenomegaly, hepatomegaly, pancytopenia. Recently, severe forms have been diagnosed in HIV positive patients. Human herpesvirus type 8 (HHV-8) DNA sequences detected peripheral blood mononuclear cells (PBMCs) patients with Kaposi's sarcoma MCD,...