Autonomous Discovery of Functional Small Molecules

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Small molecule drugs continue to dominate Man's ability to treat disease. However, the pharmaceutical industry faces unprecedented challenges on multiple fronts. The sector is dogged by a crippling failure rate in drug discovery (over 95%), and a current cost/launch of ~£1.8bn. Around 45% of the costs fall early in drug discovery because relatively few campaigns proceed to the launch of a therapeutic product. Greater innovation is urgently required to address the sector's grand challenge of improving productivity.The binding of a drug to its target protein is broadly analogous to the fitting of a key into a lock. A major challenge is to optimise the structure of the drug so that it complements its target protein perfectly. Current practices rely on the synthesis of many molecules that are then individually purified and then tested for improved biological function. Many cycles are required to discover a molecule with optimal properties, and much effort is expended in the synthesis and purification of poorly active compounds. Optimisation is thus lengthy, laborious and resource-intensive. My fellowship will enable me to develop an autonomous platform for the discovery of functional molecules. The approach will exploit chemistry that enables the function of many different molecules to be explored in parallel, in order to determine features are important for biological activity. The whole discovery approach will be automated, with the functions of the products in one round directly informing the design of reactions in the next round. Unlike most medicinal chemistry approaches, products will only be purified and identified when exciting improved biological activity is detected. The approach is thus remarkably efficient because resources are focused overtly on only those reactions that yield molecules with improved function. The resulting molecules may serve as highly innovative starting points for drug discovery programmes. I will show that my novel approach can support complementary strategies for functional molecule discovery. Crucially, I will demonstrate that it can enable the discovery of ligands - "keys" - for a range of increasingly challenging, medicinally-relevant, target protein. This activity will ensure that my novel approach is fully appreciated by scientists engaged in small molecule discovery. To ensure alignment with future discovery needs, I will collaborate with two major pharmaceutical companies and engage extensively with a wide range of drug discovery organisations. At the end of the project, I will define a mechanism that will ensure that my approach is accessible to end-users in discovery-based industries. Thus, I will ensure that my novel platform can facilitate the discovery of future drug candidates.