Effective Reaction-Based De Novo Strategy for Kinase Targets: A Case Study on MERTK Inhibitors.

Reaction-based de novo design is the computational generation of novel molecular structures by linking building blocks using reaction vectors derived from chemistry knowledge. In this work, we first adopted a recurrent neural network (RNN) model to generate three groups of building blocks with different functional groups and then constructed an in silico target-focused combinatorial library based on chemical reaction rules. Mer tyrosine kinase (MERTK) was used as a study case. Combined with a scaffold enrichment analysis, 15 novel MERTK inhibitors covering four scaffolds were achieved. Among them, compound 5a obtained an IC 50 value of 53.4 nM against MERTK without any further optimization. The efficiency of hit identification could be significantly improved by shrinking the compound library with the fragment iterative optimization strategy and enriching the dominant scaffold in the hinge region. We hope that this strategy can provide new insights for accelerating the drug discovery process.