Exploring the Druggable Conformational Space of Protein Kinases Using AI-Generated Structures.

Greater abundance of kinase structural data in inactive conformations, currently lacking in structural databases, would improve our understanding of how protein kinases function and expand drug discovery and development for this family of therapeutic targets. Modern approaches utilizing artificial intelligence and machine learning have potential for efficiently capturing novel protein conformations. We provide evidence for a bias within AlphaFold2 and ESMFold to predict structures of kinases in their active states, similar to their overrepresentation in the PDB. We show that lowering the AlphaFold2 algorithm's multiple sequence alignment depth can help explore kinase conformational space more broadly. It can also enable the prediction of hundreds of kinase structures in novel conformations, many of whose models are likely viable for drug discovery.