We describe a new toolkit for drug discovery that combines a method to identify synthetically feasible reaction paths for a molecule with virtual combinatorial synthesis. The workflow begins with the analysis of a compound against a collection of fifty very common reactions leading to the prediction of a number of potential reaction pathways with user-controllable depth. Then, using a library of commercially available or in-house building blocks it is possible to explore targeted or very large virtual libraries of compounds likely to be synthetically accessible by performing a virtual combinatorial synthesis using the chosen paths. In this way one can easily perform core hops, examine the equivalent of R-group substitutions, or generate massive libraries of compounds simply by picking a desired reaction path.<br/><br/>The toolkit is being used as the first step of a virtual screening workflow which has produced successful results in virtual screeening campaigns at Schrödinger. For example, in a recent project, starting from an 80 μM HTS hit, the results of a combinatorial enumeration as described above were used as inputs for docking, MM/GBSA scoring and FEP+ calculations which ultimately resulted in the top three compounds being synthesized, all of which, at 2 - 30 μM, were significantly more active than the original hit.

Easy exploration of synthetically accessible chemical space via synthesis-aware enumeration

256th National Meeting (2018)

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