Drug discovery is an expensive and time consuming process, with few novel drugs being approved each year. Improving methods in drug discovery for the purpose of aiding compound optimisation is an important consideration in the design of novel drugs. Matched molecular pairs (MMPs) are used for the purpose of understanding SAR as well as optimising compounds in terms of their physicochemical properties where chemists replace one functional group for another (in the same location). In this study, we analyse the most frequently observed transformations from the year 2000 for internal projects within AstraZeneca. Analysing all transformations in a selected set of projects that occur at least 100 times in total, showed that a total of 960 unique transformations were performed. The structural changes (transformations) were analysed and showed of these 960 unique transformations, there was 81 unique functional groups that were the starting point in the transformation (as in the functional group that was transformed from) and 197 unique functional groups that were the end points of the transformation (as in the functional groups that were transformed to). Analysing the functional groups in terms of their frequency shows that the more frequent the functional group occurs, the most likely it is to be transformed to another frequently occurring functional group. The transformations vary between environments such as aromatic and aliphatic systems. When analysing the effects of compound chemistry on assay results, the percentage of increasing and decreasing the property value as well as the average property change amount varies depending on the transformation, system and atomic environment. For example the 5 th most frequently occurring transformation performed on the 5th most frequently occurring atomic environments in aliphatic systems shows a that it will most frequently increase Caco2 assay results but decrease them the majority of the time when performed on the 8th most frequently occurring atomic environment. Overall, this study analyses how chemists optimise compounds in lead optimisation within large pharma.

Analysing matched molecular pair transformations in drug discovery projects as a function of time and molecular environment

256th National Meeting (2018)

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