Virtual Screening and Design with Machine Intelligence Applied to Pim-1 Kinase Inhibitors

Abstract

Ligand-based virtual screening of large compound collections, combined with fast bioactivity determination, facilitate the discovery of bioactive molecules with desired properties. Here, chemical similarity based machine learning and label-free differential scanning fluorimetry were used to rapidly identify new ligands of the anticancer target Pim-1 kinase. The three-dimensional crystal structure complex of human Pim-1 with ligand bound revealed an ATP-competitive binding mode. Generative de novo design with a recurrent neural network additionally suggested innovative molecular scaffolds. Results corroborate the validity of the chemical similarity principle for rapid ligand prototyping, suggesting the complementarity of similarity-based and generative computational approaches.

Keywords: artificial intelligence; crystal structure; de novo design; drug discovery; neural network.