Search arXiv⌕ Search
Home/Archive/arXiv

arXiv · 2601.18716

Conditioned Generative Modeling of Molecular Glues: A Realistic AI Approach for Synthesizable Drug-like Molecules

Naeyma N. Islam·Thomas R. Caulfield
View original source ↗Read source document ↗Export metadata ↓

Abstract

Alzheimer's disease (AD) is marked by the pathological accumulation of amyloid beta-42 (Abeta-42), contributing to synaptic dysfunction and neurodegeneration. While extracellular amyloid plaques are well-studied, increasing evidence highlights intracellular Abeta-42 as an early and toxic driver of disease progression. In this study, we present a novel, AI-assisted drug design approach to promote targeted degradation of Abeta-42 via the ubiquitin-proteasome system (UPS), using E3 ligase-directed molecular glues. We systematically evaluated the ternary complex formation potential of Abeta-42 with three E3 ligases: CRBN, VHL, and MDM2, through structure-based modeling, ADMET screening, and docking. We then developed a Ligase-Conditioned Junction Tree Variational Autoencoder (LC-JT-VAE) to generate ligase-specific small molecules, incorporating protein sequence embeddings and torsional angle-aware molecular graphs. Our results demonstrate that this generative model can produce chemically valid, novel, and target-specific molecular glues capable of facilitating Abeta-42 degradation. This integrated approach offers a promising framework for designing UPS-targeted therapies for neurodegenerative diseases.

Explore related subjects

cs.AIq-bio.BM

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Naeyma N. Islam, Thomas R. Caulfield. 2026-01-26. Conditioned Generative Modeling of Molecular Glues: A Realistic AI Approach for Synthesizable Drug-like Molecules. https://doi.org/10.3390/biom15060849

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related papers

arXiv2026

Small Language Models are the Future of Agentic AI

Large language models (LLMs) are often praised for exhibiting near-human performance on a wide range of tasks and valued for their ability to hold a general conversation. The rise of agentic AI systems is, however, ushering in a mass of applications in which language models perform a small number of specialized tasks repetitively and with little variation. Here we lay out the position that small language models (SLMs) are sufficiently powerful, inherently more suitable, and necessarily more economical for many invocations in agentic systems, and are therefore the future of agentic AI. Our argumentation is grounded in the current level of capabilities exhibited by SLMs, the common architectures of agentic systems, and the economy of LM deployment. We further argue that in situations where general-purpose conversational abilities are essential, heterogeneous agentic systems (i.e., agents invoking multiple different models) are the natural choice. We discuss the potential barriers for the adoption of SLMs in agentic systems and outline a general LLM-to-SLM agent conversion algorithm. Our position, formulated as a value statement, highlights the significance of the operational and economic impact even a partial shift from LLMs to SLMs is to have on the AI agent industry. We aim to stimulate the discussion on the effective use of AI resources and hope to advance the efforts to lower the costs of AI of the present day. Calling for both contributions to and critique of our position, we commit to publishing all such correspondence at https://research.nvidia.com/labs/lpr/slm-agents.

cs.AI↗
arXiv2026

EndoCogniAgent: Closed-Loop Agentic Reasoning with Self-Consistency Validation for Endoscopic Diagnosis

Endoscopic diagnosis is an iterative process in which clinicians acquire, compare, and verify local visual evidence before reaching a conclusion. Current AI systems do not adequately support this process because fine-grained evidence acquisition and multi-step reasoning remain weakly coupled, complicating reconciliation of image-derived findings with their textual interpretations. This gives rise to two failure modes, hallucinated evidence and uncorrected error accumulation, that undermine diagnostic reliability. We propose EndoCogniAgent, a closed-loop agentic framework that formulates endoscopic diagnosis as a controlled state update process for integrating complementary visual and textual evidence. At each reasoning round, a central planner selects an evidence acquisition action, specialized expert tools extract spatial and semantic observations as structured textual evidence, and a self-consistency validation mechanism examines this evidence along two dimensions, knowledge consistency against the input image and temporal consistency with prior validated findings, before updating the diagnostic state. Validated observations are admitted into the evolving state to condition subsequent planning, while insufficiently supported or conflicting findings are retained with corrective feedback that redirects the planner toward additional verification. We further introduce EndoAgentBench, a workflow-oriented benchmark comprising 6,132 question-answer pairs from 11 endoscopic datasets, to evaluate diagnostic agents across a comprehensive diagnostic chain, from fine-grained visual perception to high-level diagnostic reasoning. EndoCogniAgent achieves 85.23% overall accuracy on perception tasks and 71.13% clinical acceptance rate on reasoning tasks. Blinded clinician evaluation further shows consistent improvements in diagnostic response quality over the evaluated baselines.

cs.AI↗
arXiv2026

Ultra Strong Machine Learning: LLM-Generated Explanations Do Not Yet Suffice for Teaching Humans Active Learning Strategy

Active learning is a general learning mechanism shared by artificial and human learners. Whether AI can teach humans such a strategy that transfers across domains is an open question. Ultra Strong Machine Learning (USML), a system whose explanations quantifiably improve human out-of-sample performance compared to self-learning, is uniquely positioned to answer this question. Prior USML work relied on hand-crafted explanation templates that require expert effort for each new domain and do not scale. We developed an explanation pipeline combining Inductive Logic Programming (ILP) with large language models (LLMs) to automate explanation generation and scoring. We tested whether these explanations achieve USML in a human trial teaching active learning strategies across three related domains. Our exploratory results show that concise, expert-written explanations benefit learners with higher initial performance, while pipeline-generated explanations provide no advantage over self-learning despite being rated as higher quality from an LLM-as-judge evaluation. This case study reveals a systematic gap that LLM quality metrics do not predict human learning outcomes. Our findings point to explanation complexity relative to task difficulty as a key factor, and call for explanation methods and evaluation criteria grounded in human cognitive constraints rather than LLM preference.

cs.AI↗