Combining Artificial Intelligence and Human Expertise in Pursuit of Novel PolQ Inhibitors.

Application of generative AI, synergistically with traditional knowledge-based approaches, has expedited the discovery of small-molecule PolQ polymerase domain inhibitors. Leveraging AI-generated ligand designs, a structurally diverse set of compounds were synthesized and evaluated, ultimately identifying a novel oxime-based scaffold as a promising starting point. Although the initial hit demonstrated only modest biochemical potency, the oxime moietyan unexplored vector in this chemical spaceoffered an opportunity for strategic substitution. Gratifyingly, using this strategy, a highly potent array of functionalized oxime PolQ inhibitors displaying promising initial ADME properties was delivered, underscoring the power of generative AI to unlock new chemical space and accelerate lead optimization.