As a specialist chemistry CRO (contract research organization) focused on chirally-pure chemical space, Liverpool ChiroChem, LCC, prides itself on its understanding of asymmetric synthesis. In addressing drug discovery needs from hit identification to lead optimization, LCC approached us to help them develop their virtual libraries to share with biotech and pharmaceutical clients worldwide.

Given our domain expertise, we worked closely with LCC’s scientists to establish the schemes covering six chemical reactions that would be performed in-house. Some of these reactions were straightforward (e.g., amide couplings), while others required special handling. For example (see figure below):

1. Different stereoisomers that can be generated during a reaction (e.g., N-alkylation through reductive amination).
2. Some synthons, like the diamine below, contained more than one synthetic handle. We virtually tagged the reactive atom, facilitating the relevant transformations and avoiding unwanted side products.

We used our proprietary platform, mainly REACT2D, to virtually run the six reactions and generate 1.3M unique products while retaining crucial stereochemical information. The synthon, the commercial building block, and the reaction route are encoded for each product within a unique ID to easily determine how to make any of these molecules in the lab.

The resultant virtual library was filtered for drug-like properties, unwanted reactive groups, and duplicates. Distributions of key physico-chemical properties were then generated with Forecaster. We also investigated similarities to the SureChEMBL patent space and provided some clustered subsets for quicker browsing.

The LCC team is now maintaining the library and its current version is available at www.liverpoolchirochem.com/3discovery-virtual-library.

Synthesis of the physical hits can now be carried out in LCC’s parallel synthesis lab in the UK.