Chillin' in Flatland - Development of HCIE (Heterocycle Isostere Explorer)

The 2009 publication "Escape from flatland" shows a correlation between a success of potential leads in clinical trials and the presence of sp3 hybridised carbons, suggesting that more 3D molecules have a better chance of becoming drugs, possibly due to their higher solubility and better fit with the 3D protein cavities. However, since then it has been shown that flat core scaffolds are equally good starting points for accessing 3D shape space as 3D core scaffolds. This suggest that the 3D shape desired for increased success in drug discovery could be achieved through a choice of substitutes and functional groups, while still keeping the aromatic, flat scaffold cores. That is a desirable prospect, as the chemistry required to introduce sp3 hybridised carbons is more challenging and time-consuming. Moreover, the chemistry of small, aromatic heterocycles is still largely unexplored as shown by the creation of VEHICLe - virtual exploratory heterocyclic library. VEHICLe is a database of theoretically possible heteroaromatic ring systems, consisting of around 25000 molecules. At the time of its creation, in 2008, only 1701 of those systems (around 7%) have been synthesized and reported in literature. However, the authors' analysis has shown that more than 3000 additional molecules in the database are predicted to be synthetically tractable. This shows a potential for new chemical space exploration and introduction of new chemical structures in design of chemical probes and drugs with unique molecular architectures, while using the already known and simpler chemistry of heterocycles. The aim of this project would be to develop a computational tool, the HeteroCycle Isostere Explorer (HCIE) to discover new heterocyclic cores for compound optimisation in chemical probe development and drug discovery. The main function of HCIE would be to search the VEHICLe database for heterocycle bioisosteres using shape, electrostatic potential and vector similarity. This method of suggesting isosteres distinguishes HCIE from other isostere search tools, like SwissBioisostere, in that it doesn't require any previous knowledge of bioisosteric replacements to make its predictions and thus will to lead to novel isostere suggestions. Additionally, the VEHICLe database would be analysed to search for areas of "flatland" that are currently underexplored and could present novel physicochemical property spaces. Lastly, software to analyse the synthetic tractability and predict synthesis routes for heterocycles in VEHICLe would be developed and incorporated into HCIE, helping the user to incorporate novel heterocycles into their target molecules and de novo design software. Those predictions would then be validated by attempting to synthesize some of the not previously synthesized heterocycles in VEHICLe. This project falls within the following EPSRC research areas: Computational and theoretical chemistry, Chemical biology and biological chemistry and Synthetic organic chemistry. It would be supervised by Professors Paul Brennan and Fernanda Duarte and conducted in collaboration with Exscientia.

The UK's world-leading position in biomedical research is critically dependent upon training scientists with the cutting-edge research skills and technological know-how needed to drive future scientific advances. Since 2009, the EPSRC and MRC CDT in Systems Approaches to Biomedical Science (SABS) has been working with its consortium of 22 industrial and institutional partners to meet this training need.

Over this period, our partners have identified a growing training need caused by the increasing reliance on computational approaches and research software. The new EPSRC CDT in Sustainable Approaches to Biomedical Science: Responsible and Reproducible Research - SABS:R^3 will address this need. By embedding a sustainable approach to software and computational model development into all aspects of the existing SABS training programme, we aim to foster a culture change in how the computational tools and research software that now underpin much of biomedical research are developed, and hence how quantitative and predictive translational biomedical research is undertaken.

As with all CDT Programmes, the future impact of SABS:R^3 will be through its alumni, and by the culture change that its training engenders. By these measures, our existing SABS CDT is already proving remarkably successful. Our alumni have gone on to a wide range of successful careers, 21 in academic research, 19 in industry (including 5 in SABS partner companies) and the other 10 working in organisations from the Office of National Statistics to the EPSRC. SABS' unique Open Innovation framework has facilitated new company connections and a high level of operational freedom, facilitating 14 multi-company, pre-competitive, collaborative doctoral research projects between 11 companies, each focused on a SABS student.

The impact of sustainable and open computational approaches on biomedical research is clear from existing SABS' student projects. Examples include SAbDab which resulted from the first-ever co-sponsored doctorate in SABS, by UCB and Roche. It was released as open source software, is embedded in the pipelines of several pharmaceutical companies (including UCB, Medimmune, GSK, and Lonza) and has resulted in 13 papers. The SABS student who developed SAbDab was initially seconded to MedImmune, sponsored by EPSRC IAA funding; he went on to work at Roche, and is now at BenevolentAI. Similarly, PanDDA, multi-dataset X-ray crystallographic software to detect ligand-bound states in protein complexes is in CCP4 and is an integral part of Diamond Light Source's XChem Pipeline. The SABS student who developed PanDDA was awarded an EMBO Fellowship.

Future SABS:R^3 students will undertake research supported by both our industrial partners and academic supervisors. These supervisors have a strong track record of high impact research through the release of open source software, computational tools, and databases, and through commercialisation and licensing of their research. All of this research has been undertaken in collaboration with industrial partners, with many examples of these tools now in routine use within partner companies.

The newly focused SABS:R^3 will permit new industrial collaborations. Six new partners have joined the consortium to support this new bid, ranging from major multinationals (e.g. Unilever) to SMEs (e.g. Lhasa). SABS:R^3 will continue to make all of its research and teaching resources publicly available and will continue to help to create other centres with similar aims. To promote a wider cultural change, the SABS:R^3 will also engage with the academic publishing industry (Elsevier, OUP, and Taylor & Francis). We will explore novel ways of disseminating the outputs of computational biomedical research, to engender trust in the released tools and software, facilitate more uptake and re-use.