Integrated computational and synthetic tools to drive the discovery of orthosteric protein-protein interaction inhibitors

Small molecule drugs continue to dominate our collective ability to treat disease. However, the pharmaceutical industry faces challenges on several fronts, and increasing productivity has been framed as the grand challenge for the sector. Against a background of increasingly cost-constrained healthcare systems, the cost of launching new drugs is increasingly high (recently estimated at £1.8 Bn for each new drug!). In order to improve productivity in drug discovery, it is necessary to develop innovative new medicines that address currently unmet medical needs. Protein-protein interactions represent a significant untapped, but challenging, opportunity for treating diseases including cancer, inflammatory disease, cardiovascular disease and infection.

Drugs function by binding to a protein target within the body. Most existing small molecule drugs bind to well-defined pockets in proteins - analogous to a key fitting into a lock. In stark contrast, the design of drugs to inhibit protein-protein interactions generally requires a fundamentally different type of interaction of the drug with its protein target - analogous to a hand gripping a ball. Thus, the development of effective drugs that target protein-protein interactions raises new challenges that need to be met in future drug discovery. This programme will develop new tools and understanding that will facilitate future drug discovery against protein-protein interactions.

We will develop computational tools to classify protein-protein interactions according to their underlying 3D structure and the probability that they can be inhibited using small molecules. We will then exploit these computational tools to design classes of small molecule that can be prepared readily using state-of-the-art synthetic methods, and that are predisposed to target different types of protein-protein interaction. The resulting small molecule inhibitors will be made available to biological researchers to help understand the role of protein-protein interactions in disease. In addition, the new tools will be made accessible to the research community to facilitate the early-stage discovery of small molecule drugs that target protein-protein interactions.

The programme will benefit from the input of major pharmaceutical companies, smaller drug discovery companies, a not-for-profit drug discovery organisation, and international academics. The involvement of a wide range of experts is essential because of the increasing trend for early stage drug discovery to be conducted by a range of organisations (both industry and academic), especially for more challenging target classes. Thus, together with wider research community engagement, we will ensure that the required future capabilities for early-stage drug discovery against protein-protein interactions are met.

The pharmaceutical industry is the UK's third largest exporting sector (exports: £17B/yr), and maintains a leading global position having brought many of the world's leading drugs to the market. However, the sector faces multiple challenges on multiple fronts e.g. regulatory changes and increasingly cost-constrained healthcare systems. Increasing productivity is the grand challenge for the pharmaceutical sector. To ensure alignment with drug discovery needs, the programme will draw on the expertise of different types of organisation that are engaged in early-stage drug discovery.

Protein-protein interactions (PPIs) offer a remarkable opportunity to increase innovation in early-stage drug discovery. This opportunity stems from the huge number of PPIs and their central role in healthy/ disease biology. This programme will address fundamental scientific impediments to progress in PPI inhibitor discovery. New computational tools and small molecule scaffolds will be developed to drive the discovery of cell-permeable inhibitors across a very broad range of PPI classes. The programme will open medium term opportunities to commercialise tools and longer term opportunities to address currently unmet clinical needs (e.g. such small-molecule drugs can generate sales >£1Bn). Through engagement with stakeholders in this area of research (e.g. academics, pharmaceutical scientists, other end-users and policy makers), effective pathways will be developed to commercialise or translate the research outputs to ensure that they become available. The outputs will include an online searchable PPI database; new computational tools to facilitate PPI inhibitor discovery; scaffolds/libraries that target specific PPI topologies; and high quality chemical PPI probes. Thus, this programme has the potential to impact upon a major UK sector; and, ultimately, the provision of healthcare. In addition to non-academic end-users of the research, basic scientists will exploit the new knowledge and tools to increase understanding of PPI-mediated biological mechanisms.

The team members will expand and enrich their knowledge and competencies through the programme to help transition to future careers in science. The postdoctoral researchers and PhD students who, as part of an interdisciplinary team, will develop new cutting-edge research and transferrable skills that map onto future drug-discovery needs. They will have the opportunity to undertake appropriate secondments e.g. in industry or at internationally-leading laboratories. They will also benefit from the superb research and training environments at Leeds and Bristol e.g. through interaction in targeted activities with local and international PhD training programmes.

The programme represents an opportunity to engage the general public at all age levels: the topic will serve as a vehicle to enthuse and educate the lay public as it raises many of the challenges facing modern drug discovery and hence future healthcare provision. Innovative activities that will engage the general public include comic strips, science fair exhibitions and a video documentary.

The objectives of the innovative Pathway to Impact are:

(i) to ensure alignment of the programme with future needs in drug discovery;

(ii) to secure pathways to commercialise / translate research outputs;

(iii) to train exceptional and versatile early career researchers; and

(iv) to engage the general public.