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This review provides a comprehensive synthesis of structure-aware molecular modeling from a task-centric perspective, focusing on binding pocket identification, interaction prediction, pose estimation, and complex modeling. We highlight the technological evolution from traditional docking and scoring frameworks toward geometry-informed deep learning architectures that encode protein structures via surface geometry, equivariant representations, and multi-modal embeddings. Special attention is given to recent progress in structure-conditioned molecular generation. We classify generative approaches into four core strategies: sequence-based generation with 3D conditioning, fragment-based linking and growing, graph-based generation under structural constraints, and 3D coordinate\u2013based generation including diffusion models. Each paradigm balances chemical validity, spatial fidelity, and computational tractability in distinct ways, with diffusion-based and point cloud models emerging as powerful tools for synthesizing pocket-complementary molecules in full 3D space. We also discuss the emergence of co-folding models, which unify protein folding and ligand binding into a single predictive framework, bridging the gap between sequence-level learning and structural resolution. Finally, we examine the key challenges of data scarcity, generalization, and multi-objective control, and outline future directions toward scalable, interpretable, and physically plausible generation pipelines. By tracing how structural knowledge is reshaping AI-driven drug design, this review aims to provide both a conceptual roadmap and practical insight into next-generation molecular modeling.<\/jats:p>","DOI":"10.1093\/bib\/bbag081","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T12:46:33Z","timestamp":1770209193000},"source":"Crossref","is-referenced-by-count":7,"title":["Structure-informed machine learning for drug discovery: a task-centric perspective"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0495-6512","authenticated-orcid":false,"given":"Yi","family":"Li","sequence":"first","affiliation":[{"name":"College of Mathematics and Computer Science, Dali University , No. 2 Hongsheng Road, Dali 671003 ,","place":["China"]},{"name":"College of Agriculture and Biological Science, Dali University , No. 2 Hongsheng Road, Dali 671003 ,","place":["China"]},{"name":"Key Laboratory of Bioinformatics and Computational Biology, Department of Education of Yunnan Province, Dali University , No. 2 Hongsheng Road, Dali 671003 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong-hui","family":"Zhan","sequence":"additional","affiliation":[{"name":"College of Mathematics and Computer Science, Dali University , No. 2 Hongsheng Road, Dali 671003 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxin","family":"Rao","sequence":"additional","affiliation":[{"name":"Drug Discovery and Design Center , State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zu Chongzhi Road, Pudong New Area, Shanghai 201203,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengting","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Agriculture and Biological Science, Dali University , No. 2 Hongsheng Road, Dali 671003 ,","place":["China"]},{"name":"Key Laboratory of Bioinformatics and Computational Biology, Department of Education of Yunnan Province, Dali University , No. 2 Hongsheng Road, Dali 671003 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Sang","sequence":"additional","affiliation":[{"name":"College of Agriculture and Biological Science, Dali University , No. 2 Hongsheng Road, Dali 671003 ,","place":["China"]},{"name":"Key Laboratory of Bioinformatics and Computational Biology, Department of Education of Yunnan Province, Dali University , No. 2 Hongsheng Road, Dali 671003 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1014-2558","authenticated-orcid":false,"given":"Xin","family":"Zeng","sequence":"additional","affiliation":[{"name":"College of Mathematics and Computer Science, Dali University , No. 2 Hongsheng Road, Dali 671003 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