AlphaFold Accelerates Artificial Intelligence Powered Drug Discovery: Efficient Discovery of a Novel Cyclin-dependent Kinase 20 (CDK20) Small Molecule Inhibitor (2201.09647v2)

Abstract: The AlphaFold computer program predicted protein structures for the whole human genome, which has been considered as a remarkable breakthrough both in AI application and structural biology. Despite the varying confidence level, these predicted structures still could significantly contribute to structure-based drug design of novel targets, especially the ones with no or limited structural information. In this work, we successfully applied AlphaFold in our end-to-end AI-powered drug discovery engines constituted of a biocomputational platform PandaOmics and a generative chemistry platform Chemistry42, to identify a first-in-class hit molecule of a novel target without an experimental structure starting from target selection towards hit identification in a cost- and time-efficient manner. PandaOmics provided the targets of interest and Chemistry42 generated the molecules based on the AlphaFold predicted structure, and the selected molecules were synthesized and tested in biological assays. Through this approach, we identified a small molecule hit compound for CDK20 with a Kd value of 8.9 +/- 1.6 uM (n = 4) within 30 days from target selection and after only synthesizing 7 compounds. Based on the available data, the second round of AI-powered compound generation was conducted and through which, a more potent hit molecule, ISM042-2 048, was discovered with a Kd value of 210.0 +/- 42.4 nM (n = 2), within 30 days and after synthesizing 6 compounds from the discovery of the first hit ISM042-2-001. To the best of our knowledge, this is the first reported small molecule targeting CDK20 and more importantly, this work is the first demonstration of AlphaFold application in the hit identification process in early drug discovery.