{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T01:47:42Z","timestamp":1762652862045,"version":"build-2065373602"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62422113","62271329"],"award-info":[{"award-number":["62422113","62271329"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shenzhen Science and Technology","award":["20231129091450002"],"award-info":[{"award-number":["20231129091450002"]}]},{"name":"Shenzhen Polytechnic University Research Fund","award":["6024310027K","6022310036K"],"award-info":[{"award-number":["6024310027K","6022310036K"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U22A2037","62425204","62122025","62450002","62432011"],"award-info":[{"award-number":["U22A2037","62425204","62122025","62450002","62432011"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Beijing Natural Science Foundation","doi-asserted-by":"publisher","award":["L248013"],"award-info":[{"award-number":["L248013"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>Deep generative methods based on language models have the capability to generate new data that resemble a given distribution and have begun to gain traction in ligand design. However, existing models face significant challenges when it comes to generating ligands for unseen targets, a scenario known as zero-shot learning. The ability to effectively generate ligands for novel targets is crucial for accelerating drug discovery and expanding the applicability of ligand design. Therefore, there is a pressing need to develop robust deep generative frameworks that can operate efficiently in zero-shot scenarios.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In this study, we introduce ZeroGEN, a novel zero-shot deep generative framework based on protein sequences. ZeroGEN analyzes extensive data on protein\u2013ligand inter-relationships and incorporates contrastive learning to align known protein-ligand features, thereby enhancing the model\u2019s understanding of potential interactions between proteins and ligands. Additionally, ZeroGEN employs self-distillation to filter the initially generated data, retaining only the ligands deemed reliable by the model. It also implements data augmentation techniques to aid the model in identifying ligands that match unseen targets. Experimental results demonstrate that ZeroGEN successfully generates ligands for unseen targets with strong affinity and desirable drug-like properties. Furthermore, visualizations of molecular docking and attention matrices reveal that ZeroGEN can autonomously focus on key residues of proteins, underscoring its capability to understand and generate effective ligands for novel targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>The source code and data of this work is freely available in the https:\/\/github.com\/viko-3\/ZeroGEN.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaf572","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T13:46:07Z","timestamp":1760449567000},"source":"Crossref","is-referenced-by-count":0,"title":["ZeroGEN: leveraging language models for zero-shot ligand design from protein sequences"],"prefix":"10.1093","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3521-475X","authenticated-orcid":false,"given":"Yangyang","family":"Chen","sequence":"first","affiliation":[{"name":"College of Computer Science and Electronic Engineering, Hunan University , Changsha, Hunan 410082,","place":["P.R. China"]}]},{"given":"Zixu","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Computer Science and Electronic Engineering, Hunan University , Changsha, Hunan 410082,","place":["P.R. China"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5971-046X","authenticated-orcid":false,"given":"Pengyong","family":"Li","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology, Xidian University , Xian 710071,","place":["P.R. China"]}]},{"given":"Li","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of AIDD, Shanghai Yuyao Biotechnology Co., Ltd. , Shanghai 201109,","place":["P.R. China"]}]},{"given":"Xiangxiang","family":"Zeng","sequence":"additional","affiliation":[{"name":"College of Computer Science and Electronic Engineering, Hunan University , Changsha, Hunan 410082,","place":["P.R. 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