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While several generative models have been proposed for lead optimization under multi\u2010property constraints, they still struggle to balance multi\u2010objective optimization with sufficient scaffold\u2010level exploration. To address this challenge, we present SMarT\u2010Diff (Scaffold\u2010based Multi\u2010property Tuning Diffusion), a generative diffusion model that achieves this balance by reinventing scaffold hopping\u2014enabling both property optimization and structural novelty. SMarT\u2010Diff achieved superior performance across diverse molecular generation and optimization metrics. Notably, across both single\u2010target (LRRK2, HPK1, GLP\u20101R) and dual\u2010target (GSK3\u03b2\/JNK3) molecular optimization tasks, the model consistently generated drug\u2010like molecules exhibiting enhanced structural diversity, preserved pharmacophoric features, and high synthetic accessibility. Furthermore, wet\u2010lab validation of our model\u2010generated compounds against LRRK2 identified a highly promising candidate with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 1.544\u00a0nM, which surpasses even the positive control LRRK2\u2010IN\u20101. This result not only confirms the compound's exceptional potency but also demonstrates the strong real\u2010world potential of our model to drive the design and optimization of novel, highly effective drug candidates.\n                  <\/jats:p>","DOI":"10.1002\/advs.75674","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T08:17:47Z","timestamp":1778833067000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diffusion\u2010Based Generative Model With Scaffold\u2010Hopping Strategy Yields Highly Potent Bioactive Molecules"],"prefix":"10.1002","volume":"13","author":[{"given":"Yuwei","family":"Yang","sequence":"first","affiliation":[{"name":"Faculty of Applied Sciences Macao Polytechnic University  Macao SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqing","family":"Gong","sequence":"additional","affiliation":[{"name":"Faculty of Applied Sciences Macao Polytechnic University  Macao SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shukai","family":"Gu","sequence":"additional","affiliation":[{"name":"Faculty of Applied Sciences Macao Polytechnic University  Macao SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Faculty of Applied Sciences Macao Polytechnic University  Macao SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Liu","sequence":"additional","affiliation":[{"name":"Faculty of Applied Sciences Macao Polytechnic University  Macao SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Tian","sequence":"additional","affiliation":[{"name":"Faculty of Applied Sciences Macao Polytechnic University  Macao SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4422-4968","authenticated-orcid":false,"given":"Qianqian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Faculty of Applied Sciences Macao Polytechnic University  Macao SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojun","family":"Yao","sequence":"additional","affiliation":[{"name":"Faculty of Applied Sciences Macao Polytechnic University  Macao SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9284-3667","authenticated-orcid":false,"given":"Huanxiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Faculty of Applied Sciences Macao Polytechnic University  Macao SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201005905\u2010z"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42256\u2010025\u201000997\u2010w"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201034692\u2010w"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010019\u20100224\u2010x"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1086"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c11686"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010019\u20100050\u20103"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2024.103992"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.1608"},{"key":"e_1_2_9_11_1","volume-title":"ICML'24 Workshop ML for Life and Material Science: From Theory to Industry Applications","author":"Dorna V.","year":"2024"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201046569\u20101"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.5c00591"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43588\u2010025\u201000886\u20107"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42256\u2010024\u201000916\u20105"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btae260"},{"key":"e_1_2_9_17_1","unstructured":"J.Yu Y.Zheng H. 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