Drug-target binding kinetics has recently emerged as a critical parameter in determining the in vivo efficacy and toxicity of lead compounds. Unfortunately, the rational optimisation of this parameter to design more effective and less toxic drugs is extremely difficult as the features of small ligands and their protein targets that affect binding kinetics remain poorly understood. The aim of this project is to systematically fill this knowledge gap by combining state of the art computational approaches. We propose to combine our state-of-the-art enhanced sampling and QM/MM methods to compute reliable association free energy profiles and rationalise the binding kinetics of receptor-ligand complexes in terms of the structures and energies of the transition state ensemble. We will test and validate these methods, which have not been previously combined for this purpose. Together, they tackle the two central challenges of biomolecular simulation, i.e. conformational sampling and accuracy of potentials. We will apply the techniques we develop to well-characterised biomolecular systems of real biomedical importance, such as the influenza target neuraminidase, the anti-cancer targets p38a, Abl, Src and FGFr tyrosine-kinases, the chaperone HSP90, and other drug targets in collaboration with our pharmaceutical industrial partners (UCB, GSK and Sanofi). The results will shed new light on the kinetics of drug binding and their molecular origins. The methods we develop should find wide application, and we will make them available and accessible.

Understanding how small organic molecules pack together to form crystalline solids is a fundamental scientific challenge. Not only can the same molecule often pack in more than one way ( polymorphism ), but other molecules, often water, can be involved in the structure, significantly increasing the variety of solid forms. It is particularly important for the pharmaceutical industry to understand the solid-state behaviour of the drug molecules they produce, since the different solid forms often have different dissolution rates and so different pharmaceutical characteristics. Drug regulatory agencies require that the physical properties of the form used to be fully characterised, and uncharacterised forms may provide loopholes in patent protection. Solvates (that is solid forms including water or other solvent molecules) are widely used when anhydrous forms are unsuitable (e.g. prone to change form over time). However, the physical properties of hydrates vary widely: some are very stable, others tend to lose solvent and become amorphous. Trying to predict how a given material will behave is a fundamental scientific challenge.This proposal aims to remove some of this mystery by using nuclear magnetic resonance (NMR) to identify and characterise solvent molecules in solid forms. Other techniques, such as X-ray diffraction are able to identify solvent molecules that are relatively immobile, but struggles with the (interesting) cases where the solvent molecules are in motion. In contrast, NMR experiments are usually very sensitive to the effects of motion. We will be concentrating on applying new techniques for hydrogen NMR (both 1H and 2H), which is generally difficult in solids. In this case, however, we are interested in looking at the role of hydrogens in the structure ( hydrogen bonding ) and hydrogens in motion, and we believe that identifying the solvent signals will be feasible. This will be complemented by computational work to calculate the quantities we measure experimentally. This will allow us to better relate what we measure to structural features e.g. the length of hydrogen bonds. We will be studying a number of systems, chosen in collaboration with partners in academia and the pharmaceutical industry, which show different behaviour. Fully characterising the structural role and mobility of the solvent (and related features, such as hydrogen bonding), using solid-state NMR together with complementary techniques (such as X-ray diffraction), will make a major contribution towards understanding the behaviour of solvate forms. As well as answering fundamental scientific questions, this will be of great benefit to the pharmaceutical industry as they try to predict the suitability of different solid forms in advance, rather wasting time and money on forms that later turn out to be badly behaved.

Vaccines are the most successful public health initiative of the 20th century. They save millions of lives annually, add billions to the global economy and extended life expectancy by an average of 30 years. Even so, the UN estimates that globally 6 million children each year die before their 5th birthday. While vaccines do exist to prevent these deaths, it is limitations in manufacturing capacity, technology, costs and logistics that prevent us for reaching the most vulnerable. The UK is a world leader in vaccine research and has played a significant leadership role in several public health emergencies, most notably the Swine Flu pandemic in 2009 and the recent Ebola outbreak in West Africa. While major investment has been made into early vaccine discovery - this has not been matched in the manufacturing sciences or capacity. Consequently, leading UK scientists are forced to turn overseas to commercialise their products. Therefore, this investment into The Future Vaccine Manufacturing Hub will enable our vision to make the UK the global centre for vaccine discovery, development and manufacture. We will create a vaccine manufacturing hub that brings together a world-class multidisciplinary team with decades of cumulative experience in all aspects of vaccine design and manufacturing research. This Hub will bring academia, industry and policy makers together to propose radical change in vaccine development and manufacturing technologies, such that the outputs are suitable for Low and Middle Income Countries. The vaccine manufacturing challenges faced by the industry are to (i) decrease time to market, (ii) guarantee long lasting supply - especially of older, legacy vaccine, (iii) reduce the risk of failure in moving between different vaccine types, scales of manufacture and locations, (iv) mitigating costs and (v) responding to threats and future epidemics or pandemics. This work is further complicated as there is no generic vaccine type or manufacturing approach suitable for all diseases and scenarios. Therefore this manufacturing Hub will research generic tools and technologies that are widely applicable to a range of existing and future vaccines. The work will focus on two main research themes (A) Tools and Technologies to de-risk scale-up and enable rapid response, and (B) Economic and Operational Tools for uninterrupted, low cost supply of vaccines. The first research theme seeks to create devices that can predict if a vaccine can be scaled-up for commercial manufacture before committing resources for development. It will include funds to study highly efficient purification systems, to drive costs down and use genetic tools to increase vaccine titres. Work in novel thermo-stable formulations will minimise vaccine wastage and ensure that vaccines survive the distribution chain. The second research theme will aim to demystify the economics of vaccine development and distribution and allow the identification of critical cost bottlenecks to drive research priorities. It will also assess the impact of the advances made in the first research theme to ensure that the final cost of the vaccine is suitable for the developing world. The Hub will be a boon for the UK, as this research into generic tools and technologies will be applicable for medical products intended for the UK and ensure that prices remain accessible for the NHS. It will establish the UK as the international centre for end-to-end vaccine research and manufacture. Additionally, vaccines should be considered a national security priority, as diseases do not respect international boundaries, thus this work into capacity building and rapid response is a significant advantage. The impact of this Hub will be felt internationally, as the UK reaffirms its leadership in Global Health and works to ensure that the outputs of this Hub reach the most vulnerable, especially children.