OpenADMET: Embracing the Avoid-Ome to Transform Drug Discovery

Drug discovery faces significant obstacles posed by unpredictable pharmacokinetic and safety properties, necessitating a complex, multiparameter optimization process. ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) issues remain the primary reason for failure in drug development, with over 90% of discovery compounds failing basic ADME standards and unexpected ADMET problems causing around 30% of clinical setbacks. Conventional approaches that mainly rely on broad molecular properties offer limited guidance because they lack detailed insight into the atomic-level interactions between drugs and the body’s complex systems. Transforming small-molecule drug discovery requires a systematic, detailed understanding of the "Avoid-ome": the broad set of proteins that influence ADME and toxicity characteristics. The Avoid-ome includes a finite, manageable set of enzymes, transporters, receptors, and channels, which must be treated as "anti-targets" and avoided during the design process. OpenADMET (https://openadmet.org), an international open-science initiative, aims to fill the critical ADMET data gap by creating pre-competitive, open datasets covering metabolism, transport, distribution, and toxicity. The initiative is developing platforms that make compound synthesis, measurements (using technologies like scaled mass spectrometry and synthetic biology), and data analysis more affordable and capable of high-throughput processing. This approach uses high-throughput structural biology to ensure models are based on mechanistic, atomistic understanding, helping to clarify the structural basis of outliers, species differences, and genetic variation. Additionally, an active learning workflow is used across diverse chemical spaces to select compounds that are the most informative for building generalizable predictive models. OpenADMET includes blind community challenges, inspired by CASP and SAMPL, to evaluate predictive models with unreleased data, encouraging rigorous assessment and ongoing improvement within the research community. By systematically studying the Avoid-ome and creating open, structural, and mechanistic datasets, OpenADMET establishes a foundation for a new era of rational drug design, demonstrating that the most effective way to improve drug discovery is to stop avoiding the Avoid-ome and instead study it directly.