In order to discover a new medicine, academic and industrial researchers require access to diverse collections of molecules. However, the slow step in medicine discovery is the synthesis of these biologically active molecules from simpler building blocks. In many cases, key molecules are inaccessible with current technologies, which prevents researchers exploring the full range of chemical structures required to understand and develop a new medicine. Around 80% of the molecules used in the drug discovery process contain a nitrogen atom (in the form of amines), and therefore novel methods that generate new amine structures are highly valued in the drug discovery arena. In this project, we will explore the unique reactivity of organoboranes to develop a novel and general catalytic platform for the synthesis of amines. Organoboranes have an unusual ability to abstract hydride from amines, generating a reactive cationic intermediate and a hydride bound to boron. This unique reactivity will allow common and readily available building blocks to be used in novel processes. The methods discovered in the project will be easy to use and not require special training. It will also generate low waste through high atom economy. The project will demonstrate the utility of these new tools to targeted end-users in academia, and pharmaceutical and supporting Contract Research industries, by solving specific challenges in drug discovery. For example, by addressing limitations in the synthesis of nitrogen-containing molecules, we will enable access to new and previously inaccessible structures. This will transform medicinal and biological chemists' abilities by enabling them to develop clear pictures of structure-activity relationships that are critical for studying disease and developing new treatments. The project is divided into three Aims that represent the three reaction classes where we will employ the unique abilities of organoboranes to solve challenges. - Aim 1 will target the first direct and modular synthesis of privileged aryl alkyl amines found in serotonergic/dopaminergic pharmaceuticals that treat a variety of mental illnesses. This Aim will enable efficient access to aryl alkyl amines and allow a full and systematic study of how structure affects activity and therefore lead to more efficacious treatments. - Aim 2 will develop a new approach to the catalytic alpha CH arylation of amines. We will demonstrate utility of this method in the late-stage-functionalisation of a variety of validated medicines so that new or improved bioactivity can be efficiently discovered from known molecular templates. - Aim 3 will develop a new approach to the synthesis of a common class of bioactive N- heterocycles, tetrahydroquinolines. We will address specific limitations of current methods and will enable the rapid exploration of chemical space for structure activity relationships related to treatments for cancer, pain, osteoporosis, parasite infections and allergies for the first time.

Molecular sciences, such as chemistry, biophysics, molecular biology and protein science, are vital to innovations in medicine and the discovery of new medicines and diagnostics. As well as making a crucial contribution to health and society, industries in this field provide an essential component to the economy and contribute hugely to employment figures, currently generating nearly 500,000 jobs nationally. To enable and facilitate future economic growth in this area, the CDT will provide a cohort of researchers who have training in both aspects of this interface who will be equipped to become the future innovators and leaders in their field. All projects will be based in both molecular and medical sciences and will focus on unmet medical needs, such as understanding of disease biology, identification of new therapeutic targets, and new approaches to discovery and development of novel therapies. Specific problems will be identified by researchers within the CDT, industrial partners, stakeholders and the CDT students. The research will be structured around three theme areas: Biology of Disease, Molecule and Assay Design and Structural Biology and Computation. The CDT brings together leading researchers with a proven track record across these areas and who have pioneered recent advances in the field, such as multiple approved cancer treatments. Their combined expertise will provide supervision and mentorship to the student cohort who will work on projects that span these research themes and bring their contributions to bear on the medical problems in question. The student cohort approach will allow teams of researchers to work together on joint projects with common goals. Projects will be proposed between academics, industrial partners and students with priority given to those with industrial relevance. The programme of research and training across the disciplines will equip graduates of the CDT with an unprecedented background of knowledge and skills across the disciplines. The programme of research and training across the disciplines will be supplemented by training and hands-on experiences of entrepreneurship, responsible innovation and project management. Taken together this will make graduates of the CDT highly desirable to employers, equip them with the skills they need to envisage and implement future innovations in the area and allow them to become the leaders of tomorrow. A structured and highly experienced management group, consisting of a director, co-directors, theme leads and training coordinators will oversee the execution of the CDT with the full involvement of industry partners and students. This will ensure delivery of the cohort training programme and joint events as well as being accountable for the process of selection of projects and student recruitment. The management team has an established track record of delivery of research and training in the field across industry and academia as well as scientific leadership and network training coordination. The CDT will be delivered as a single, fully integrated programme between Newcastle and Durham Universities, bringing together highly complementary skills and backgrounds from the two institutions. The seamless delivery of the programme across the two institutions is enabled by their unique connectivity with efficient transport links and established regional networks. The concept and structure of the CDT has been developed in conjunction with the industrial partners across the pharmaceutical, biotech and contract research industries, who have given vital steer on the desirability and training need for a CDT in this area as well as to the nature of the theme areas and focus of research. EPSRC funding for the CDT will be supplemented by substantial contributions from both Universities with resources and studentship funding and from industry partners who will provide training, in kind contribution and placements as well as additional studentships.

This Open Fellowship Plus application focusses on discovery, development and innovation enabling precision molecule editing and diversification, an area central to drug discovery and of great interest to our pharmaceutical industry partners. It also looks to examine and address diversity across the science + engineering community involved in translation, with a particular focus on the largest population grouping (women) who remain significantly under-represented in spinouts and start-ups. The formation of C-X bonds (where X is F, Cl, Br, or I) is of great importance to the pharmaceutical and agrochemical industries. The introduction of a halogen into a molecule can be used to modulate bioactivity, bioavailability and metabolic stability. It also provides a chemically reactive and selectively functionalisable handle, that can be used to build or diversify molecules. For these reasons >81% of agrochemicals contain a C-X bond, and for pharmaceuticals >26% contain a C-Cl bond with a further 67% requiring a C-Cl bond for assembly. Current industrial approaches to making C-X bonds still require Cl2 and Br2. Such approaches rely on fragile supply chains with much of the elemental halides being generated through energy expensive processes in India, China, Russia, Ukraine, and require the C-X bond to be introduced at an early stage. Most critically, these approaches lack selectivity and, even when applied to simple starting materials, result in hard to separate mixtures. For this reason, only simple halogenated building blocks are generated. To incorporate a halogen into a molecule, whether that be a pharmaceutical or agrochemical, its assembly must be designed using these simple halogenated building blocks. Transitioning from current thinking to new thinking + discovery In contrast to current industrial approaches to halogenation, enzymes confer exquisite selectivity, enabling precision late-stage halogenation. Unlike current industrial approaches, salt is used as halogenating agent, only one product is generated simplifying purification, and complex bioactive scaffolds, rather than simple building blocks, can be accepted as substrates. In this ambitious fellowship proposal, we will: - use bioinformatics approaches, coupled to wet screening and AI to discover new halogenases - develop and apply AI guided directed evolution and selection to these new halogenases - explore innovative new approaches to cofactor recycling toward enabling reaction intensification and scale up - demonstrate precision late-stage diversification of pharmaceutically relevant scaffolds, developing new and innovative diversification procedures. Demonstrating PRIMED for Diversification in the context of pharmaceutical design and discovery. The proposed work is poised to bring significant advantage and acceleration to molecule making and diversification, particularly in the context of drug discovery. It will also bring benefit to biocatalysts through the development and pioneering of AI informed enzyme selection. Further insight and benefit will be brought through the Open Plus component, shining a light on diversity data within the translational arena.

The switch from traditional organic solvents, many of which are hazardous, volatile or non-sustainable, to modern green solvents is one of the key sustainability objectives in High Value Chemical Manufacture. Currently, the use of green solvents is often explored at process development stage, instead of discovery stage. This necessitates re-optimisation of processes, due to changes in yield, selectivity, impurity profile and purification. These lead to longer development time, cost, and additional uncertainty. On the other hand, selecting the right solvent early may enhance chemoselectivity, avoid additional reaction steps, and simplify purification of the products. Predicting these changes is an important underpinning capability for wider adaptation of green solvents in manufacturing. Unfortunately, the scarcity of reaction data in green solvents is a key obstacle in developing this capability. Thus, there is an urgent need for ML models which predict reactivity in green solvents based on available data in traditional solvents. In addition to addressing the short time-scale of early-stage process development, these will increase the confidence in utilising green solvents at discovery stage, support sophisticated synthetic routes planning tools which takes into account side products, impurity and purification methods, and act as valuable regulatory tools for assessing hazardous impurities. This project will address these challenges through the following objectives: O1 Addressing the scarcity of reactivity data in the literature through curation of reaction data with reliable reaction time and inclusion of rate laws. O2 Developing solvent-dependent reactivity and reaction selectivity prediction models for green solvents. O3 Producing a set of standard substrates based on cheminformatics analysis of industrially relevant reactions and collecting their reactivity data in green solvents. These outputs will have transformative impacts in the chemical manufacture industry, delivering rapid, more sustainable and better quality-controlled processes through shorter development time, and confidence in predicting reaction outcomes in green solvents. The project will be carried out with support from industrial partners working in the field of cheminformatics and AI/Machine learning, e.g. Lhasa Ltd. and Molecule One. Its outputs will be guided and exploited by partners who are end-users in the High Value Chemical Manufacturing sectors: AstraZeneca, CatSci, and Concept Life Science.

This proposal builds directly upon a BBSRC FoF awarded in 2020 toward the translation of enzymatic methods of carbon halogen bond formation. Context: Over 20% of pharmaceuticals, including drugs such as Clarityn, require a carbon chlorine bond. A carbon halogen bond, conveniently referred to as a C-X bond by chemists (where X is typically chlorine, bromine, or iodine), imparts improved activity and bioavailability. Drugs containing this "X-factor" are used to treat medical conditions such as cancer, diabetes, high cholesterol, stomach ulcers, anaemia, asthma, epilepsy, and others. This C-X bond provides a useful handle for tuning the pharmaceutical's activity and bioavailability profiles, its installation is, therefore, essential to drug discovery. Furthermore, this C-X bond is a chemically reactive and orthogonal handle, a gateway to almost any chemical diversification imaginable. The construction of over 90% of small molecule pharmaceuticals is thus reliant on carbon-chlorine bond formation. Current chemical halogenation methods lack selectivity. Our enzyme technology can be used to precisely place a C-X bond at just the position required. Scope: We are paving the way for spinning out X-Genix; a company that provides bespoke technology enabling precision molecule editing. The award of a BBSRC FoF in 2020 has enabled us to develop our technology and carry out customer discovery, identifying pharmaceutical drug discovery as our beachhead market. Our ambition is to partner with the pharmaceutical industry to deliver precision molecule editing for drug discovery. Here, as we prepare for spin out, we will deliver the following Commercial and Technical objectives (C1- C4, and T1-T4 respectively): 1. Details C1. Extend and deepen our engagement with Pharma: We are already in discussions with team leaders, CEOs, and/or CSO/CTOs in over 20 pharmaceutical and fine chemical companies in the UK and internationally. Through components of this project, especially C2, we will deepen existing relationships. Through links with CEFIC and EFPIA, we will increase our number of industry partnerships. C2. Deliver proof of concept projects: Testing the selection and utilisation of halogenases for molecules of interest to Astra Zeneca and Concept/Malvern, provided under confidentiality agreements. These studies will showcase the technology and will be key to refining our commercial offering, poising the team and technology to deliver commercial contracts by the end of the grant. C3. Refine Business Plan: By building on insight from C1& C2, developments in T3, and through mentoring from UK and international advisors. C4. Investor-Ready Proposition for Seed Funding: This project prepares X-Genix to be investor ready. Working in partnership with international investors and advisors we will further develop our pitch deck and investment ask. T1. Extend our portfolio of halogenases to 200: Ensuring a robust and diverse toolbox of biocatalysts. T2. Refine and prepare for filing a further patent on our halogenase selection and optimisation technology: Focusing on developments that enable expeditious discovery of an enzyme capable of regioselectively functionalising a given substrate. T3. Extend our IP, showcasing our technology on medicinally relevant compounds within our own drug discovery program: Further growing investable value. Benefiting from the considerable med chem expertise across our team and advisory board, and levering technology advancements from T1/T2 this aspect will become a main focus of X-Genix. This focus is based on advice received throughout our early business development work. T4. Explore intensifying and scaling reactions: We will further develop our technology, exploring reaction intensification and scaling.