Generative deep learning-driven de novo design of targeted MAP4K6 inhibitors

The discovery of selective small-molecule inhibitors for pharmacologically underexplored kinases remains a critical barrier to precision drug development, particularly under data-sparse conditions, where ligand annotations are scarce. Here, we present MolEvoRNN, a generative deep learning (GDL) model that enables the de novo design of chemically valid, structurally diverse, and target-adapted compounds in low-data regimes. Through transfer learning and temperature-controlled sampling, MolEvoRNN efficiently navigates the kinase-relevant chemical space while preserving scaffold novelty, drug-likeness, and synthetic tractability. Applied to MAP4K6, a poorly characterized serine/threonine kinase implicated in hepatocellular carcinoma (HCC), MolEvoRNN generated >49,000 chemically valid molecules with >80% novel Bemis-Murcko scaffolds. MolEvoRNN outperformed the baseline GDL models across key generative metrics, including diversity (1.00), uniqueness (1.00), novelty (1.00), and internal diversity (0.869), demonstrating broad chemical exploration with minimal redundancy. A multilayered virtual screening cascade combining QSAR modeling, pharmacophore mapping, molecular docking, MM-GBSA binding energy estimation, and 1000 ns molecular dynamics simulations identified three lead candidates MINK-5730, MINK-13510, and MINK-16516 with high predicted affinity, favorable ADMET properties, and robust dynamic stability. Unlike end-to-end optimization pipelines, MolEvoRNN decouples generation from evaluation, promoting methodological transparency and rigorous post-hoc triaging. This study establishes a scalable, generalizable paradigm for rational small-molecule design in underexplored target spaces, bridging generative deep learning with structural pharmacology to accelerate early-phase therapeutic discovery.