# MolSC: Leveraging Substituent Contributions to Enhance Fine-grained Molecular Understanding in LLMs

arXiv: https://arxiv.org/abs/2609.23073 · HTML: https://mlsanity.com/paper/2609.23073/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 21 of its 49 references that are in the map.
- First posted on arXiv 19 Sep 2026.

## Builds on (most cited first, 21 of 21)

- [Efficient Memory Management for Large Language Model Serving with PagedAttention](https://mlsanity.com/paper/2309.06180/) (2023)
- [LlamaFactory: Unified Efficient Fine-Tuning of 100+ Language Models](https://mlsanity.com/paper/2403.13372/) (2024)
- [MoleculeNet: A Benchmark for Molecular Machine Learning](https://mlsanity.com/paper/1703.00564/) (2017)
- [ChemCrow: Augmenting large-language models with chemistry tools](https://mlsanity.com/paper/2304.05376/) (2023)
- [ChemBERTa: Large-Scale Self-Supervised Pretraining for Molecular Property Prediction](https://mlsanity.com/paper/2010.09885/) (2020)
- [Translation between Molecules and Natural Language](https://mlsanity.com/paper/2204.11817/) (2022)
- [LlaSMol: Advancing Large Language Models for Chemistry with a Large-Scale, Comprehensive, High-Quality Instruction Tuning Dataset](https://mlsanity.com/paper/2402.09391/) (2024)
- [Unifying Molecular and Textual Representations via Multi-task Language Modelling](https://mlsanity.com/paper/2301.12586/) (2023)
- [BioT5+: Towards Generalized Biological Understanding with IUPAC Integration and Multi-task Tuning](https://mlsanity.com/paper/2402.17810/) (2024)
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- [UniMoT: Unified Molecule-Text Language Model with Discrete Token Representation](https://mlsanity.com/paper/2408.00863/) (2024)
- [LLaMo: Large Language Model-based Molecular Graph Assistant](https://mlsanity.com/paper/2411.00871/) (2024)
- [Multimodal Molecular Pretraining via Modality Blending](https://mlsanity.com/paper/2307.06235/) (2023)
- [HIGHT: Hierarchical Graph Tokenization for Molecule-Language Alignment](https://mlsanity.com/paper/2406.14021/) (2024)
- [3D-MolT5: Leveraging Discrete Structural Information for Molecule-Text Modeling](https://mlsanity.com/paper/2406.05797/) (2024)
- [Enhancing Chemical Reaction and Retrosynthesis Prediction with Large Language Model and Dual-task Learning](https://mlsanity.com/paper/2505.02639/) (2025)
- [KnowMol: Advancing Molecular Large Language Models with Multi-Level Chemical Knowledge](https://mlsanity.com/paper/2510.19484/) (2025)
- [MELT: Materials-aware Continued Pre-training for Language Model Adaptation to Materials Science](https://mlsanity.com/paper/2410.15126/) (2024)
- [Omni-Mol: Multitask Molecular Model for Any-to-any Modalities](https://mlsanity.com/paper/2502.01074/) (2025)
- [Bridging the Gap Between Molecule and Textual Descriptions via Substructure-aware Alignment](https://mlsanity.com/paper/2510.26157/) (2025)

## Abstract (arXiv)

Recent advances in natural language processing have led to molecular Large Language Models (LLMs) with strong performance across diverse chemistry tasks. However, they still struggle to capture fine-grained structure-property relationships, particularly how small, localized modifications alter a molecule's behavior. To address this limitation, we introduce MolSC, a dataset of substituent contributions, defined as property changes induced by attaching specific substituents to molecular scaffolds. Curated from manually annotated bioactivity records, MolSC spans structural-alert liability, target-specific bioactivity, and physicochemical descriptors, and contains 181K substituent-level examples for training. We further propose MolSC-Bench, a held-out evaluation benchmark of 1,541 examples disjoint from MolSC at the scaffold, substituent, and molecule levels. Our experiments show that existing molecular LLMs and strong proprietary models such as GPT-5.2 and Gemini-3-Flash show limited reliability in substituent contribution prediction. In contrast, training on MolSC substantially improves this ability and achieves strong performance across diverse downstream molecular tasks. These results highlight substituent contribution learning as a key component of fine-grained molecular understanding.