Drug Discovery

Scientific discovery is driven by scientists generating novel hypotheses for complex problems that undergo rigorous experimental validation. To augment this process, we introduce Co-Scientist, a multi-agent AI system built on Gemini for structured scientific thinking and hypothesis generation. Co-Scientist aims to help scientists discover new original knowledge. Conditioned on their research objectives and prior scientific evidence, it formulates demonstrably novel research hypotheses for experimental verification. The system's design involves agents continuously generating, critiquing and refining hypotheses accelerated by scaling test-time compute. Key contributions include: (1) a multi-agent architecture with an asynchronous task execution framework for flexible compute scaling; (2) a tournament evolution process for self-improving hypotheses generation. Automated evaluations show continued benefits of test-time compute scaling, improving hypothesis quality over time. While general purpose, we focus the validation in three biomedical applications: drug repurposing, novel target discovery, and explaining mechanisms of anti-microbial resistance. Specifically, Co-Scientist helped identify new drug repurposing candidates and synergistic combination therapies for acute myeloid leukemia, which were validated through in vitro experiments. These real-world validations demonstrate the potential of Co-Scientist to accelerate scientific discovery and usher in an era of AI empowered scientists.

Background: Neurosymbolic (NeSy) artificial intelligence describes the combination of logic or rule-based techniques with neural networks. Compared to neural approaches, NeSy methods often possess enhanced interpretability, which is particularly promising for biomedical applications like drug discovery. However, no clear guidelines exist to assess the biological plausibility of model interpretations. Methods: To assess interpretability in the context of drug discovery, we devise a novel prediction task, called drug mechanism-of-action (MoA) deconvolution, with an associated, tailored knowledge graph (KG), MoA-net. We then develop the MoA Retrieval System (MARS), a NeSy approach for drug discovery which leverages logical rules with learned rule weights. Results: Using MARS' interpretable features alongside domain knowledge, we find that MARS and other NeSy approaches on KGs are susceptible to reasoning shortcuts, in which the prediction of true labels is driven by ``degree-bias'' rather than the domain-based rules. Subsequently, we demonstrate ways to identify and mitigate this. Thereafter, MARS achieves performance on par with current state-of-the-art models while producing model interpretations aligned with known MoAs. Conclusion: Through MARS, we showcase the novel task of computational MoA deconvolution. Our results emphasize the importance of using interpretable models, like NeSy ones, for applications in drug discovery. Specifically, by identifying and mitigating reasoning shortcuts, MARS MoA predictions which are biologically meaningful and, therefore, more reliable for downstream drug discovery research.

Molecular optimization, the process of designing molecules with desirable properties, represents a critical challenge in drug discovery. The recent advancements in large language models (LLMs) have opened new opportunities for their integration with traditional molecular optimization algorithms to improve performance. In this work, we propose Molecular Language Model powered Evolutionary Algorithm (Mol-E), an evolutionary algorithm that relies on the generative capabilities of LLMs trained on molecules and molecular properties. Scientific Contribution. Mol-E obtains the highest aggregate Top-10 AUC among the comparable full-23-task results considered here, scoring 17.500 in the task-agnostic regime, in which the oracle is treated strictly as a black box, and 20.551 in the task-informed regime, in which the optimizer receives a fixed semantic description of the objective. Mol-E also improves over the evaluated baselines on multi-property optimization with docking against DRD2, MK2, and AChE.

Clinical trials bridge basic research and clinical application, serving as essential steps in drug development. This review examines clinical trial phases (Phase I [safety assessment], Phase II [efficacy evaluation], Phase III [large-scale validation], and Phase IV [post-marketing surveillance]), highlighting the distinct characteristics and interconnections. Major challenges are identified, including ethical compliance, participant recruitment, and ensuring diversity and representativeness in trial populations, while proposing evidence-based mitigation strategies. To address these challenges, innovative technologies, such as artificial intelligence, big data analytics, and digital health tools, are transforming trial design and implementation, enhancing efficiency and data quality. Looking forward, the review explores how emerging therapies, including gene therapy and immunotherapy, are reshaping trial design requirements and emphasizes the growing importance of regulatory harmonization and global collaboration. Clinical trials remain central to advancing innovative drug development and improving patient outcomes.