MolBioKG: Grounding Out-of-Graph Molecules in Biomedical Knowledge Graphs via Multi-Resolution Structural Anchoring

Biomedical knowledge graphs (KGs) accelerate drug discovery, but standard pipelines assume query molecules already exist as graph entities, leaving unregistered molecules disconnected. We address this cold-start challenge, termed the out-of-graph molecule problem, by introducing MolBioKG. This two-layer system grounds unseen molecules in biomedical evidence via multi-resolution structural anchoring. It connects an index of 2.74 million molecules (represented by scaffolds, fragments, functional groups, and fingerprints) to a 9.6-million-edge KG. Given only a SMILES string, MolBioKG retrieves structurally related graph entities and traverses their biomedical neighborhoods without task-specific training. It features two inference mechanisms: static multi-anchor retrieval using Reciprocal Rank Fusion, and Adapt-KG, a tool-using LLM policy for adaptive traversal. Evaluated across in-graph link recovery, complex multi-hop reasoning, and out-of-graph generalization, MolBioKG outperforms strong baselines. Notably, it raises Hits@10 from 0.585 to 0.876 in multi-hop reasoning and out-of-graph target recall from 0.145 to 0.269, all while ensuring predictions retain traceable structural anchors and source-attributed KG evidence.

Pepti-drift: Toxicity-Repulsive Drifting for Antigen-Conditioned Discrete Peptide Generation

Peptides are a promising therapeutic modality that combine the chemical tunability of small molecules with the target specificity of macromolecular therapeutics. However, designing antigen-specific binding peptides while avoiding toxicity remains a major challenge for therapeutic peptide discovery. Here, we present Pepti-drift, a toxicity-aware latent refinement framework that generates peptide candidates through a single antigen-conditioned drift step. In a peptide embedding space, Pepti-drift learns to attract generated peptide latents toward antigen-matched binding peptides while repelling them from toxicity-associated regions. This is challenging because binding-promoting physicochemical features often overlap with toxicity-associated features in peptide representation space. To address this, we introduce a warm-up strategy to stabilize this competing objective by first learning binding-oriented attraction and then increasing toxicity repulsion. Pepti-drift achieves highly efficient generation, running 16.2-fold faster than PepMLM and 1,092.0-fold faster than PepTune. Generated peptides show 100% validity, 98.1% uniqueness, the highest sequence diversity, and near-zero cross-antigen reuse. Further evaluation indicates consistently reduced toxicity and hemolysis risk across most peptide-length ranges while retaining target-related predictive binding signal. Pepti-drift thus provides a fast, scalable, and controllable framework for antigen-specific peptide design that directly encodes safe-and-active properties.

Democratizing Drug Discovery with an Orchestrated, Knowledge-Driven Multi-Agent Team for User-Guided Therapeutic Design

Therapeutic discovery remains a formidable challenge, impeded by the fragmentation of specialized domains and the execution gap between computational design and physiological validation. Although generative AI offers promise, current models often function as passive assistants rather than as autonomous executors. Here, we introduce OrchestRA, a human-in-the-loop multi-agent platform that unifies biology, chemistry, and pharmacology into an autonomous discovery engine. Unlike static code generators, our agents actively execute simulations and reason the results to drive iterative optimization. Governed by an Orchestrator, a Biologist Agent leverages deep reasoning over a massive knowledge graph (>10 million associations) to pinpoint high-confidence targets; a Chemist Agent autonomously detects structural pockets for de novo design or drug repositioning; and a Pharmacologist Agent evaluates candidates via rigorous physiologically based pharmacokinetic (PBPK) simulations. This architecture establishes a dynamic feedback loop where pharmacokinetic and toxicity profiles directly trigger structural reoptimization. By seamlessly integrating autonomous execution with human guidance, OrchestRA democratizes therapeutic design, transforming drug discovery from a stochastic search to a programmable evidence-based engineering discipline.