Empowering Chemical Structures with Biological Insights for Scalable Phenotypic Virtual Screening

Motivation: The scalable identification of bioactive compounds is essential for contemporary drug discovery. This process faces a key trade-off: structural screening offers scalability but lacks biological context, whereas high-content phenotypic profiling provides deep biological insights but is resource-intensive. The primary challenge is to extract robust biological signals from noisy data and encode them into representations that do not require biological data at inference. Results: This study presents DECODE (DEcomposing Cellular Observations of Drug Effects), a framework that bridges this gap by empowering chemical representations with intrinsic biological semantics to enable structure-based in silico biological profiling. DECODE leverages limited paired transcriptomic and morphological data as supervisory signals during training, enabling the extraction of a measurement-invariant biological fingerprint from chemical structures and explicit filtering of experimental noise. Our evaluations demonstrate that DECODE retrieves functionally similar drugs in zero-shot settings with over 20% relative improvement over chemical baselines in mechanism-of-action (MOA) prediction. Furthermore, the framework achieves a 6-fold increase in hit rates for novel anti-cancer agents during external validation. Availability and implementation: The codes and datasets of DECODE are available at https://github.com/lian-xiao/DECODE.

EDBench: Large-Scale Electron Density Data for Molecular Modeling

Existing molecular machine learning force fields (MLFFs) generally focus on the learning of atoms, molecules, and simple quantum chemical properties (such as energy and force), but ignore the importance of electron density (ED) $\rho(r)$ in accurately understanding molecular force fields (MFFs). ED describes the probability of finding electrons at specific locations around atoms or molecules, which uniquely determines all ground state properties (such as energy, molecular structure, etc.) of interactive multi-particle systems according to the Hohenberg-Kohn theorem. However, the calculation of ED relies on the time-consuming first-principles density functional theory (DFT) which leads to the lack of large-scale ED data and limits its application in MLFFs. In this paper, we introduce EDBench, a large-scale, high-quality dataset of ED designed to advance learning-based research at the electronic scale. Built upon the PCQM4Mv2, EDBench provides accurate ED data, covering 3.3 million molecules. To comprehensively evaluate the ability of models to understand and utilize electronic information, we design a suite of ED-centric benchmark tasks spanning prediction, retrieval, and generation. Our evaluation on several state-of-the-art methods demonstrates that learning from EDBench is not only feasible but also achieves high accuracy. Moreover, we show that learning-based method can efficiently calculate ED with comparable precision while significantly reducing the computational cost relative to traditional DFT calculations. All data and benchmarks from EDBench will be freely available, laying a robust foundation for ED-driven drug discovery and materials science.