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| Formato: | Preprint |
| Publicado: |
2025
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| Acceso en línea: | https://arxiv.org/abs/2512.04252 |
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| _version_ | 1866918230905323520 |
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| author | Zeng, Baichuan |
| author_facet | Zeng, Baichuan |
| contents | Predicting the inhibitory potency of small molecules against Tyrosyl-DNA Phosphodiesterase 1 (TDP1)-a key target in overcoming cancer chemoresistance-remains a critical challenge in early drug discovery. We present a deep learning framework for the quantitative regression of pIC50 values from molecular Simplified Molecular Input Line Entry System (SMILES) strings using fine-tuned variants of ChemBERTa, a pre-trained chemical language model. Leveraging a large-scale consensus dataset of 177,092 compounds, we systematically evaluate two pre-training strategies-Masked Language Modeling (MLM) and Masked Token Regression (MTR)-under stratified data splits and sample weighting to address severe activity imbalance which only 2.1% are active. Our approach outperforms classical baselines Random Predictor in both regression accuracy and virtual screening utility, and has competitive performance compared to Random Forest, achieving high enrichment factor EF@1% 17.4 and precision Precision@1% 37.4 among top-ranked predictions. The resulting model, validated through rigorous ablation and hyperparameter studies, provides a robust, ready-to-deploy tool for prioritizing TDP1 inhibitors for experimental testing. By enabling accurate, 3D-structure-free pIC50 prediction directly from SMILES, this work demonstrates the transformative potential of chemical transformers in accelerating target-specific drug discovery. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2512_04252 |
| institution | arXiv |
| publishDate | 2025 |
| record_format | arxiv |
| spellingShingle | Fine-Tuning ChemBERTa for Predicting Inhibitory Activity Against TDP1 Using Deep Learning Zeng, Baichuan Machine Learning Artificial Intelligence Predicting the inhibitory potency of small molecules against Tyrosyl-DNA Phosphodiesterase 1 (TDP1)-a key target in overcoming cancer chemoresistance-remains a critical challenge in early drug discovery. We present a deep learning framework for the quantitative regression of pIC50 values from molecular Simplified Molecular Input Line Entry System (SMILES) strings using fine-tuned variants of ChemBERTa, a pre-trained chemical language model. Leveraging a large-scale consensus dataset of 177,092 compounds, we systematically evaluate two pre-training strategies-Masked Language Modeling (MLM) and Masked Token Regression (MTR)-under stratified data splits and sample weighting to address severe activity imbalance which only 2.1% are active. Our approach outperforms classical baselines Random Predictor in both regression accuracy and virtual screening utility, and has competitive performance compared to Random Forest, achieving high enrichment factor EF@1% 17.4 and precision Precision@1% 37.4 among top-ranked predictions. The resulting model, validated through rigorous ablation and hyperparameter studies, provides a robust, ready-to-deploy tool for prioritizing TDP1 inhibitors for experimental testing. By enabling accurate, 3D-structure-free pIC50 prediction directly from SMILES, this work demonstrates the transformative potential of chemical transformers in accelerating target-specific drug discovery. |
| title | Fine-Tuning ChemBERTa for Predicting Inhibitory Activity Against TDP1 Using Deep Learning |
| topic | Machine Learning Artificial Intelligence |
| url | https://arxiv.org/abs/2512.04252 |