MEGA-CL: A Molecular Foundation Model for Generalizable ADMET Prediction through Graph External Attention and Contrastive Learning

Predicting the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of small molecules remains a major challenge in drug discovery. Here, we present MEGA-CL, a foundation graph neural network framework for universal molecular ADMET prediction. MEGA-CL integrates self-supervised contrastive learning with a multi-head external attention mechanism and an enhanced message-passing architecture, enabling simultaneous modeling of local chemical substructures and global inter-graph relationships while mitigating over-smoothing effects commonly observed in deep graph networks. Across 13 benchmark datasets and 21 downstream ADMET tasks, MEGA-CL consistently outperforms state-of-the-art baseline models. In particular, the framework demonstrates robust performance on challenging regression tasks, including clearance (CL) and steady-state volume of distribution (VDss), while maintaining strong generalization ability in independent external validation. Clinically relevant predictive accuracy was achieved, with more than 75% of predictions falling within a 3-fold error range. In an external evaluation on 18 novel compounds derived from recently approved FDA drugs, over 50% of human liver microsome clearance (HLMC) predictions were within a 2-fold error range. To further assess its practical applicability, MEGA-CL was prospectively evaluated on three preclinical drug candidates using in vitro hepatic microsomal metabolism assays and CYP450 inhibition assays guided by model predictions. The predicted HLMC values for all candidates were within 2.5-fold of the experimentally measured values, and 73.3% of CYP450 inhibition endpoints (11/15) were correctly classified. These results demonstrate the potential of MEGA-CL as a generalizable framework for accelerating in silico ADMET evaluation and early-stage drug candidate optimization.

SCALE:Scalable Conditional Atlas-Level Endpoint transport for virtual cell perturbation prediction

Virtual cell models aim to enable in silico experimentation by predicting how cells respond to genetic, chemical, or cytokine perturbations from single-cell measurements. In practice, however, large-scale perturbation prediction remains constrained by three coupled bottlenecks: inefficient training and inference pipelines, unstable modeling in high-dimensional sparse expression space, and evaluation protocols that overemphasize reconstruction-like accuracy while underestimating biological fidelity. In this work we present a specialized large-scale foundation model SCALE for virtual cell perturbation prediction that addresses the above limitations jointly. First, we build a BioNeMo-based training and inference framework that substantially improves data throughput, distributed scalability, and deployment efficiency, yielding 12.51* speedup on pretrain and 1.29* on inference over the prior SOTA pipeline under matched system settings. Second, we formulate perturbation prediction as conditional transport and implement it with a set-aware flow architecture that couples LLaMA-based cellular encoding with endpoint-oriented supervision. This design yields more stable training and stronger recovery of perturbation effects. Third, we evaluate the model on Tahoe-100M using a rigorous cell-level protocol centered on biologically meaningful metrics rather than reconstruction alone. On this benchmark, our model improves PDCorr by 12.02% and DE Overlap by 10.66% over STATE. Together, these results suggest that advancing virtual cells requires not only better generative objectives, but also the co-design of scalable infrastructure, stable transport modeling, and biologically faithful evaluation.