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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\u2500an unexplored vector in this chemical space\u2500offered 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.<\/jats:p>","DOI":"10.1021\/acsomega.6c01170","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T23:40:37Z","timestamp":1783986037000},"page":"43300-43308","source":"Crossref","is-referenced-by-count":0,"title":["Combining Artificial Intelligence and Human Expertise\nin Pursuit of Novel PolQ Inhibitors"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9949-7078","authenticated-orcid":true,"given":"Ageo","family":"Miccoli","sequence":"first","affiliation":[{"name":"Sygnature Discovery Ltd. , Alderley Park , , ,","place":["Alderley Edge, Cheshire, U.K., SK10 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