Drug discovery is a long, complex and expensive process. Information related to the three-dimensional structure of macromolecular drug targets and their ligands plays a central role from drug target identification up to lead optimisation.
The use of synchrotrons is now routine in the drug discovery industry and Diamond offers world leading facilities that combine cutting edge technical instrumention, essential for de novo structure solution and the study of protein ligand interactions, with the latest developments in automation required to accelerate lead identification and ligand screening processes.
While X-ray crystallography remains a key tool to characterise macromolecules, small molecules, complexes and ligand binding, the use of complementary techniques such as electron microscopy, circular dichroism and small angle X-ray scattering is increasingly leading to a more complete understanding of the process in question. Electron microscopy has recently emerged as an alternative method to crystallography, providing structural information of macromolecules at similar resolution. Circular dichroism and small angle X-ray scattering are both excellent techniques to investigate the size, stability and conformation of macromolecules (and complexes) in solution.
Fragment Screening Platform
Solution Protein Characterisation Platform
Electron Microscopy Platform
Following the emergence of the new coronavirus SARS-CoV-2 in late 2019 which quickly developed into a pandemic, the race soon began to discover more about the virus and prevent its spread.
Building on the knowledge gained from the SARS outbreak in 2003, it is hoped that by studying the structure of the proteins in SARS-CoV-2 scientists will identify potential lead compounds and develop therapies to prevent viral infection and replication.
T-cell receptors (TCRs) are protein complexes found on the surface
of human T-cells responsible for recognising a large variety of
antigen peptides. When a TCR binds to a specific antigen it triggers
an immune response that is part of the adaptive immune system
and prevents the growth of pathogens.
There is great interest in using this natural defence system for
cancer immunotherapy by producing modified TCRs that bind
cancer antigens and activate an immune response against
Membrane proteins represent a large group of important drug targets with over 50% of approved drugs targeting these proteins within the body.
Understanding the 3D structure of membrane proteins is invaluable for target discovery, validation, and for hit optimisation. X-ray macromolecular crystallography (MX) is a principal research method for acquiring structural information on membrane proteins, but for this to be successful we require the production of good quality crystals from the target protein, or its complexes with potential drug candidates.
It is particularly difficult to produce and purify membrane proteins in sufficient yield and quality for crystallisation, and furthermore, membrane protein crystallisation itself represents a significant challenge.
The World Health Organization estimates that worldwide, annual influenza epidemics result in about 3-5 million cases of severe illness and about 250,000 to 500,000 deaths. Influenza A viruses are the most common cause of seasonal flu in humans and represent a significant risk to public health.
When the influenza virus infects a host cell, it starts to make copies of itself as the disease spreads. The protein driving this behaviour is the viral RNA polymerase which replicates the viral RNA genome and makes RNA templates for protein synthesis. In order to understand how this process works, you need to work out the structure of the RNA polymerase at the atomic level.
The thyroid is a gland located in our neck which produces iodinated hormones essential for metabolism and growth, namely thyroid hormones (TH).
An imbalance in thyroid hormone production may lead to a range of disorders including cardiovascular, foetal development, and psychiatric problems, which affect more than 5% of the population worldwide, with increasing incidence. Most commonly, people suffer from an under-active thyroid (hypothyroidism) or less frequently, an over-active thyroid (hyperthyroidism). These conditions are often related to thyroid auto-immunity and cancer.
Antibiotic resistance is an increasingly serious threat to global public health that requires action across all government sectors and society. There are high proportions of antibiotic resistance in bacteria that cause common infections, for example urinary tract infections, and it is patients with these infections caused by drug-resistant bacteria that are generally at increased risk of worse clinical outcomes and death. These patients consume more health-care resources than patients infected with the same bacteria that are drug-resistant. Developing new treatments to tackle this worldwide problem is therefore of paramount importance.Read more...
Respiratory infections are one of the biggest killers in the western world, and pneumococcal infections can range from mild to potentially deadly. Children and the elderly are most at risk, as well as those with compromised immune systems. There are approximately 90 distinct pneumococcal serotypes and, although not all cause disease, this makes treatment challenging. An effective conjugate vaccine has been available since 2001, however there has been a rise in antibiotic resistance in serotypes not covered by this conjugate vaccine and previously non-infectious serotypes are increasing in virulence. This makes treatment of pneumococcal pneumonia and less severe illnesses such as otitis media more difficult to manage. Therefore finding new approaches to combat pneumococcal disease remains a high priority.Read more...
Influenza viruses altogether affect 5%-10% of the adult population and 20-30% of children each year. These annual epidemics are estimated to result in about approximately 3 to 5 million cases of severe illness, leading to between 250,000 to 500,000 deaths around the world. Integral to viral replication, polymerases are enzymes that copy the viral genome and produce messenger RNA which is then used to make building blocks for new virus particles.Read more...
As fast Pilatus detectors have become the gold standard at Diamond’s MX beamlines, the time needed for collecting a complete dataset is now less than two minutes. This gives a user very limited time to process data and subsequently decide what would be the best strategy for collection of data from remaining crystals.Read more...
In the past two decades, fragment based drug discovery has emerged as a powerful method to discover and develop new drugs. Such strategy relies on the identification of low molecular weight compounds that bind weakly to a target. The structural information gained on fragment-target complexes provides an excellent starting point for the development of potent and selective drugs.Read more...
Methylxanthines, including caffeine, theophylline (found in tea), and theobromine (a constituent of chocolate) are among the most widely consumed substances in the world, but their effects on the brain are not fully understood. Previously published research has shown a correlation between higher intake of caffeine and lower incidence of Parkinson’s disease. Adenosine A2A receptors regulate the effects of neurotransmitters in the brain, cardiovascular and immune systems, and are of particular interest as a drug target.Read more...
Fragment-based and structure-based drug discovery programmes put a strong emphasis on frequent routine macromolecular crystallography data collection from numerous samples. Other types of projects may only need occasional data collection on a few samples or researchers may need to run an experiment they have not done before.Read more...
X-ray structural investigation of macromolecules (proteins, viruses, enzymes etc) is a complex and time consuming process where the quality of information obtained about the three-dimensional structure is strongly dependent on the quality of crystals produced. Therefore, the structures of many important targets of pharmaceutical and biotechnology industry remain unknown simply because researchers are unable to obtain crystals of sufficiently high quality or size.Read more...
Huntington’s disease (HD) is a dominantly-inherited neuropsychiatric disorder which causes severe motor dysfunction, depression and dementia. It has been known since 1993 that the disease is due to mutation of a single gene coding for huntingtin (HTT) that extends the poly-glutamine (poly-Q) repeats in the protein. Inhibiting the enzyme responsible for the cleavage of mutant HTT - thereby reducing the generation of the poly-Q fragments - could be one way of preventing neurodegeneration. Caspase-6 was identified as this processing enzyme, yet, while structures of other caspase enzymes have been studied, caspase-6 has been suggested to be this processing enzyme but, while structures of other caspase enzymes have been solved.Read more...
Macromolecular crystallography (MX) is a key asset in the development of new drugs via structure based drug discovery. This process is now widely used by the pharmaceutical industry to gain structural insights into drug targets and map interactions with ligands. However, isolating and optimising a new lead compound is a time consuming process which usually involves screening hundreds of samples.Read more...
Elastin allows tissues in humans and other mammals to stretch and return to original shape e.g. during respiration or heart beats. The schematic on the right shows how many tropoelastin monomers (blue) can selfassemble and cross-link (red) to form elastin but the structure of the soluble precursor of elastin, tropoelastin, is not well understood.Read more...
Developments on macromolecular crystallography (MX) beamlines have achieved very high throughput and microfocus X-ray facilities have made it possible to successfully collect diffraction data from samples previously considered too small or too disordered. However, when the use of microfocus beams is coupled with the small size and poor optical properties of some samples, sample alignment and detection becomes a key problem.Read more...
The size and diffraction quality of crystals remain the major limiting factors of macromolecular crystallography (MX). Many crystals of challenging targets are small, weakly diffracting and indeed extremely sensitive to manual handling. The time consuming and often damaging process of cryo-protecting, mounting and cryocooling of crystals can significantly decrease the crystal order, resolution and overall quality of the data.Read more...
Investigating the 3D structure of macromolecules by X-ray crystallography requires the production of high quality crystals, and yet this step remains a tedious and empirical task. Weak packing and high solvent content are among the most frequent factors causing a negative impact on the acquisition of suitable diffraction images. It is, therefore, useful to develop post-crystallisation methods to enhance crystal quality.Read more...
Fragment-based and structure-based drug discovery projects require regular and frequent proprietary access to macromolecular crystallography (MX) beamlines at synchrotron facilities. However, geographic location, shutdown periods, limited human resources and beamtime availability can restrict the access to such facilities.Read more...
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