ToolGrad: Efficient tool-use dataset generation with textual "gradients"
Machine Intelligence
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Computational and AI-Driven Ecosystem for Structure-Based Covalent Drug Discovery.
ConspectusThe field of covalent drug discovery has witnessed a remarkable resurgence in recent years, a trend underscored by the approval of more than 125 covalent drugs by the US FDA as of 2025, which demonstrates their immense therapeutic potential. Driven by ever-increasing computational power and vast amounts of data, deep learning (DL) is profoundly transforming numerous fields, from natural language processing to drug discovery. In the development of covalent drugs, in particular, advanced computational methods centered on data-driven approaches and artificial intelligence (AI) exhibit immense potential. The realization of this potential depends on the construction of a synergistic ecosystem. Here, we define this "ecosystem" as an integrated set of components─including (i) curated covalent-relevant databases, (ii) AI/physics-based predictive and scoring models, (iii) interoperable computational workflows spanning site identification, docking/virtual screening, and lead optimization, and (iv) closed-loop feedback that systematically incorporates experimental outcomes to update data resources and refine/validate models. This begins with the systematic collection of past experimental results to build high-quality databases. These databases, in turn, provide the foundation for developing AI-driven computational tools capable of precisely interfacing with and accelerating downstream tasks, such as molecular docking (for generating physically plausible conformations and conducting large-scale virtual screening) and lead optimization. The application of these AI tools not only guides experimental design, but the resulting key data also feed back into and enrich the databases. Furthermore, in the cutting-edge field of covalent drugs, the precise identification of "druggable" covalent sites on target proteins has emerged as another critically important downstream task.In this Account, we describe a computational and AI-driven ecosystem for structure-based covalent drug discovery and highlight our contributions to this field. By explicitly linking databases, models, workflows, and experimental feedback into a single framework, this Account moves beyond a simple inventory of individual tools to instead offer a systematic and panoramic perspective on an integrated ecosystem for covalent drug discovery, driven by data and computational engines including AI. We focus on how this ecosystem systematically addresses the challenges from covalent binding site identification to lead discovery, thereby fundamentally accelerating the development of next-generation covalent therapies. We first articulate the philosophy behind the construction and updating of covalent databases, emphasizing the necessity of high-quality data. Subsequently, we delve into a suite of cutting-edge, AI-driven computational methods, exploring the potential of deep learning in tasks such as molecular docking, covalent binding site prediction, and lead optimization. To bridge the gap between computational theory and experimental validation, we will use the discovery of potent covalent CRM1 inhibitors as a specific case study, detailing how our customized, structure-based virtual screening pipeline was utilized to achieve a seamless workflow from computational prediction to biological validation. This section is intended to offer actionable guidance for experimental researchers seeking to leverage these powerful computational tools. Finally, we highlight the limitations and potential pitfalls of this AI engine─concerns that are equally relevant when developing AI-driven covalent docking algorithms. Building on our group's recent benchmarking of AI docking methods, we objectively evaluate current performance and discuss how transformative advances such as AlphaFold3 may reshape the field.
ChargeNet: E(3) Equivariant Graph Attention Network for Atomic Charge Prediction
Atomic charge is a fundamental quantum chemical property essential for advancing drug design and discovery. Although quantum mechanics (QM) methods offer the highest level of accuracy, their computational demands scale quadratically with the number of atoms, limiting their practicality for large-scale applications. In light of this, empirical and semiempirical methods have been introduced to improve computational efficiency, albeit often at the expense of accuracy. The advent of artificial intelligence has witnessed a growing application of machine learning (ML) techniques to accelerate atomic charge predictions. However, existing ML models often suffer from low accuracy and limited generalization capabilities. To address these challenges, we introduce an advanced equivariant graph attention neural network specifically engineered to model long-range atomic electrostatic interactions with high precision. This model introduces a sophisticated global graph attention mechanism, enabling it to capture charge contributions across multiple scales. By utilizing a combination of structural symmetry-preserving transformations and multiscale attention, our approach not only preserves the inherent symmetries of molecular structures but also substantially improves the model's accuracy, generalization, and robustness in complex scenarios. Our empirical analyses demonstrate that, compared to leading baseline models, the proposed model improves charge prediction accuracy by over 40% on average across various charge-calculation schemes. Remarkably, the model achieves superior performance on the external RESP (restrained electrostatic potential) test data sets, with a 54.6% improvement over the baseline. Additionally, we evaluated our charge model under the setting of virtual screening, where it outperforms both the OPLS3 charges and baseline deep learning models across all evaluation metrics, highlighting its extensive potential for scientific discovery.
Constitutional Midtraining: Content Presence Drives Alignment Gains
Post-training alignment is often shallow, eroding under fine-tuning. It remains untested as to whether constitutional midtraining interventions can produce durable alignment when cleanly isolated from post-training. We build a 394M-token constitutional corpus from Anthropic's Constitution and apply constitutional midtraining at 120B scale, where principled, values-based content is inserted into midtraining. A 2x2 design (curriculum ordering x deliberative reasoning) was used to produce four constitutionally midtrained conditions, plus a control, which were evaluated on self-generated and established benchmarks including alignment under pressure, value conflict resolution, blackmail, and emergent misalignment. All models were evaluated across three stages: post-midtraining, post-SFT, and post-benign fine-tuning. Constitutionally midtrained models outperformed the control on alignment generalization and durability, notably on blackmail: SFT instilled a blackmail propensity in all models, but constitutional midtraining blunted it, with the advantage surviving benign fine-tuning (-17.5pp). This durability did not extend to settings that required active resistance to in-context pressure or conflict, where the advantage attenuates after SFT. The presence of constitutional content at midtraining also mattered more than its structure, and constitutional midtraining incurred no capability cost, on average, at any stage (MMLU, ARC-Easy, piqa, GSM8K). A modest amount of constitutional content at midtraining could therefore yield broad, persistent alignment gains, offering a cheap, complementary addition to SFT-centered pipelines. Code, data, and models are available.
Let the Flows Tell: Solving Graph Combinatorial Optimization Problems with GFlowNets
This paper designs Markov decision processes (MDPs) for different combinatorial problems and proposes to train conditional GFlowNets to sample from the solution space and demonstrates that GFlowNet policies can efficiently find high-quality solutions.