Computer-aided discovery of CDK16 inhibitors: a docking-augmented machine learning regression modelling approach

Cyclin-dependent kinase 16 (CDK16), a serine/threonine protein kinase, is a critical regulator of cell cycle progression, vesicle trafficking, and apoptosis. Its dysregulation is implicated in the progression of aggressive cancers, including triple-negative breast, lung, and prostate cancer, where its overexpression correlates with poor prognosis. Despite its therapeutic promise, CDK16 remains an understudied kinase lacking selective inhibitors, underscoring the need for innovative discovery approaches. This study introduces a novel computational framework that leverages multiple docked poses to augment datasets for regression-based machine learning (ML) models targeting CDK16 inhibition. This data augmentation strategy incorporated docking scores, ligand-receptor contact fingerprints (LRCFs), and conformation-sensitive physicochemical descriptors as input features. To our knowledge, this is the first application of docked pose augmentation for a regression-based drug discovery model. A systematic evaluation of eight ML algorithms across multiple docking score consensus levels identified Gradient Boosted Trees as the optimal learner. The Genetic Function Algorithm was integrated to select a minimal set of descriptors, which improved model generalizability. The resulting validated ML-QSAR model guided the generation of a robust pharmacophore model, which was used for virtual screening of the NCI and OpnMe databases. Subsequent in vitro LanthaScreen kinase assays confirmed two novel and potent CDK16 inhibitors: compound H_28 (OpnMe code: BI-831266) with an IC₅₀ of 3.5 µM, and H_33 (OpnMe code: BI-1282) with an IC₅₀ of 5.8 µM. These findings highlight the efficacy of integrating docked pose augmentation with regression modeling and experimental validation, offering a robust framework for accelerating the discovery of targeted anticancer agents.