Pharmacophore-Guided Generative Design of Novel Drug-Like Molecules
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arXiv
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| Auteurs principaux: | , , , , , |
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| Format: | Preprint |
| Publié: |
2025
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| _version_ | 1866915530541105152 |
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| author | Podplutova, Ekaterina Vepreva, Anastasia Konovalova, Olga A. Vinogradov, Vladimir Shkil, Dmitrii O. Dmitrenko, Andrei |
| author_facet | Podplutova, Ekaterina Vepreva, Anastasia Konovalova, Olga A. Vinogradov, Vladimir Shkil, Dmitrii O. Dmitrenko, Andrei |
| contents | The integration of artificial intelligence (AI) in early-stage drug discovery offers unprecedented opportunities for exploring chemical space and accelerating hit-to-lead optimization. However, docking optimization in generative approaches is computationally expensive and may lead to inaccurate results. Here, we present a novel generative framework that balances pharmacophore similarity to reference compounds with structural diversity from active molecules. The framework allows users to provide custom reference sets, including FDA-approved drugs or clinical candidates, and guides the \textit{de novo} generation of potential therapeutics. We demonstrate its applicability through a case study targeting estrogen receptor modulators and antagonists for breast cancer. The generated compounds maintain high pharmacophoric fidelity to known active molecules while introducing substantial structural novelty, suggesting strong potential for functional innovation and patentability. Comprehensive evaluation of the generated molecules against common drug-like properties confirms the robustness and pharmaceutical relevance of the approach. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2510_01480 |
| institution | arXiv |
| publishDate | 2025 |
| record_format | arxiv |
| spellingShingle | Pharmacophore-Guided Generative Design of Novel Drug-Like Molecules Podplutova, Ekaterina Vepreva, Anastasia Konovalova, Olga A. Vinogradov, Vladimir Shkil, Dmitrii O. Dmitrenko, Andrei Quantitative Methods Artificial Intelligence The integration of artificial intelligence (AI) in early-stage drug discovery offers unprecedented opportunities for exploring chemical space and accelerating hit-to-lead optimization. However, docking optimization in generative approaches is computationally expensive and may lead to inaccurate results. Here, we present a novel generative framework that balances pharmacophore similarity to reference compounds with structural diversity from active molecules. The framework allows users to provide custom reference sets, including FDA-approved drugs or clinical candidates, and guides the \textit{de novo} generation of potential therapeutics. We demonstrate its applicability through a case study targeting estrogen receptor modulators and antagonists for breast cancer. The generated compounds maintain high pharmacophoric fidelity to known active molecules while introducing substantial structural novelty, suggesting strong potential for functional innovation and patentability. Comprehensive evaluation of the generated molecules against common drug-like properties confirms the robustness and pharmaceutical relevance of the approach. |
| title | Pharmacophore-Guided Generative Design of Novel Drug-Like Molecules |
| topic | Quantitative Methods Artificial Intelligence |
| url | https://arxiv.org/abs/2510.01480 |