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Though deep learning-based 3D generative models showed promise in enhancing the efficiency of de novo drug design recently, less research and attention has garnered for structure-based lead optimization. Herein, we propose a 3D pocket-aware diffusion model named Diffleop, which explicitly incorporates the knowledge of protein-ligand binding affinity and information on covalent bonds to guide the denoising sampling process for lead optimization with enhanced binding affinity and rational properties. Specifically, the bond constraint is achieved through diffusion on fully connected molecular graphs, and the determination of atom positions, atom and bond types in each sampling step is guided by the gradient of the binding affinity that is predicted through fitting with an E(3)-equivariant expert network. The comprehensive evaluations indicated that Diffleop outperforms baseline models on lead optimization with higher affinity and more binding interactions, and can generate more drug-like molecules with more rational structures. Diffleop was further applied to optimize 5-methyl-1H-imidazole, our newly discovered lead compound targeting human glutaminyl cyclases (QCs). Three synthesized compounds exhibit substantially improved inhibitory activities against QCs, with the most effective one showing an IC50 value of 8\u00a0nM and 3.5-fold better than clinical candidate PQ912.<\/jats:p>","DOI":"10.1093\/bib\/bbaf345","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T07:59:39Z","timestamp":1751011179000},"source":"Crossref","is-referenced-by-count":3,"title":["A 3D pocket-aware lead optimization model with knowledge guidance and its application for discovery of new glutaminyl cyclase inhibitors"],"prefix":"10.1093","volume":"26","author":[{"given":"Anjie","family":"Qiao","sequence":"first","affiliation":[{"name":"School of Computer Science and Engineering, Sun Yat-sen University , No. 132 Waihuan East Road, Guangzhou 510006 , Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuting","family":"Chen","sequence":"additional","affiliation":[{"name":"West China School of Pharmacy, Sichuan University , No. 17 Southern Renmin Road, Chengdu 610041 , Sichuan,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junjie","family":"Xie","sequence":"additional","affiliation":[{"name":"School of Computer Science and Engineering, Sun Yat-sen University , No. 132 Waihuan East Road, Guangzhou 510006 , Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weifeng","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Sun Yat-sen University , No. 132 Waihuan East Road, Guangzhou 510006 , Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Sun Yat-sen University , No. 132 Waihuan East Road, Guangzhou 510006 , 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Pharmacy, Sichuan University , No. 17 Southern Renmin Road, Chengdu 610041 , Sichuan,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Computer Science and Engineering, Sun Yat-sen University , No. 132 Waihuan East Road, Guangzhou 510006 , Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0463-4249","authenticated-orcid":false,"given":"Mingyuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Guangzhou National Laboratory , No. 9 XinDaoHuanBei Road, Guangzhou International Bio Island, Guangzhou 510005 , Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongming","family":"Chen","sequence":"additional","affiliation":[{"name":"Guangzhou National Laboratory , No. 9 XinDaoHuanBei Road, Guangzhou International Bio Island, Guangzhou 510005 , Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9030-0709","authenticated-orcid":false,"given":"Jiancong","family":"Xie","sequence":"additional","affiliation":[{"name":"School of Computer Science and Engineering, Sun Yat-sen University , No. 132 Waihuan East Road, Guangzhou 510006 , Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuangjia","family":"Zheng","sequence":"additional","affiliation":[{"name":"Global Institute of Future Technology, No. 800 Dongchuan Road, Shanghai Jiao Tong University , Shanghai 200240 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6782-2813","authenticated-orcid":false,"given":"Yuedong","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Computer Science and Engineering, Sun Yat-sen University , No. 132 Waihuan East Road, Guangzhou 510006 , 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