The Dose Makes the Poison: Exposure-Aware Evaluation of Generative Drug Design

원문 초록

Generative models are increasingly used to propose molecules for drug discovery. They can produce far more candidates than can be experimentally tested, making computational selection essential. Most selection methods rely on predicted molecular properties, such as potency and toxicity, but overlook how these properties translate into drug exposure at a given dose. As a result, molecules that appear promising on paper may require impractical doses or raise safety concerns. We investigate this gap by using physiologically based pharmacokinetic (PBPK) simulations to re-evaluate molecules selected from three PARP1-targeted generative pipelines. Of 60 shortlisted molecules, seven fail to achieve sufficient target exposure, while 28% of the remaining candidates show predicted safety risks at their required dose. Moreover, 85% of candidates with an achievable dose are outperformed by molecules overlooked during static selection. These findings suggest that accounting for dose and exposure can substantially change which generated molecules are considered promising for drug development.