{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T09:38:14Z","timestamp":1778319494112,"version":"3.51.4"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T00:00:00Z","timestamp":1733270400000},"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":["62206192"],"award-info":[{"award-number":["62206192"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018542","name":"Natural Science Foundation of Sichuan Province","doi-asserted-by":"publisher","award":["2023NSFSC1408"],"award-info":[{"award-number":["2023NSFSC1408"]}],"id":[{"id":"10.13039\/501100018542","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Central Universities","award":["1082204112364"],"award-info":[{"award-number":["1082204112364"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>The burgeoning field of target-specific drug design has attracted considerable attention, focusing on identifying compounds with high binding affinity toward specific target pockets. Nevertheless, existing target-specific deep generative models encounter notable challenges. Some models heavily rely on elaborate datasets and complicated training methodologies, while others neglect the multi-constraint optimization problem inherent in drug design, resulting in generated molecules with irrational structures or chemical properties.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>To address these issues, we propose a novel framework (TargetSA) that leverages adaptive simulated annealing (SA) for target-specific molecular generation and multi-constraint optimization. The SA process explores the discrete structural space of molecules, progressively converging toward the optimal solution that fulfills the predefined objective. To propose novel compounds, we first predict promising editing positions based on historical experience, and then iteratively edit molecular graphs through four operations (insertion, replacement, deletion, and cyclization). Together, these operations collectively constitute a complete operation set, facilitating a thorough exploration of the drug-like space. Furthermore, we introduce a reversible sampling strategy to re-accept currently suboptimal solutions, greatly enhancing the generation quality. Empirical evaluations demonstrate that TargetSA achieves state-of-the-art performance in generating high-affinity molecules (average vina dock \u22129.09) while maintaining desirable chemical properties.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>https:\/\/github.com\/XueZhe-Zachary\/TargetSA<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btae730","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T18:41:55Z","timestamp":1733856115000},"source":"Crossref","is-referenced-by-count":9,"title":["TargetSA: adaptive simulated annealing for target-specific drug design"],"prefix":"10.1093","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3456-2832","authenticated-orcid":false,"given":"Zhe","family":"Xue","sequence":"first","affiliation":[{"name":"College of Computer Science, Sichuan University , Chengdu, Sichuan 610065,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenwei","family":"Sun","sequence":"additional","affiliation":[{"name":"College of Computer Science, Sichuan University , Chengdu, Sichuan 610065,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenhao","family":"Zheng","sequence":"additional","affiliation":[{"name":"College of Computer Science, Sichuan University , Chengdu, Sichuan 610065,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiancheng","family":"Lv","sequence":"additional","affiliation":[{"name":"College of Computer Science, Sichuan University , Chengdu, Sichuan 610065,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7502-7572","authenticated-orcid":false,"given":"Xianggen","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Computer Science, Sichuan University , Chengdu, Sichuan 610065,","place":["China"]},{"name":"Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University , Chengdu, Sichuan 610041,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,12,4]]},"reference":[{"key":"2025042214235746800_btae730-B1","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/s41586-021-04175-x","article-title":"Structures of the \u03c32 receptor enable docking for bioactive ligand discovery","volume":"600","author":"Alon","year":"2021","journal-title":"Nature"},{"key":"2025042214235746800_btae730-B2","first-page":"4320","article-title":"CogMol: target-specific and selective drug design for covid-19 using deep generative models","volume":"33","author":"Chenthamarakshan","year":"2020","journal-title":"Adv Neural Inf Process Syst"},{"key":"2025042214235746800_btae730-B3","author":"Du","year":"2022"},{"key":"2025042214235746800_btae730-B4","doi-asserted-by":"crossref","first-page":"4200","DOI":"10.1021\/acs.jcim.0c00411","article-title":"Three-dimensional convolutional neural networks and a cross-docked data set for structure-based drug design","volume":"60","author":"Francoeur","year":"2020","journal-title":"J Chem Inf Model"},{"key":"2025042214235746800_btae730-B5","doi-asserted-by":"crossref","first-page":"100678","DOI":"10.1016\/j.patter.2023.100678","article-title":"Computer-aided multi-objective optimization in small molecule discovery","volume":"4","author":"Fromer","year":"2023","journal-title":"Patterns"},{"key":"2025042214235746800_btae730-B600"},{"key":"2025042214235746800_btae730-B6","doi-asserted-by":"crossref","article-title":"MIMOSA: Multi-constraint molecule sampling for molecule optimization","author":"Fu","DOI":"10.1609\/aaai.v35i1.16085"},{"key":"2025042214235746800_btae730-B7","first-page":"12325","article-title":"Reinforced genetic algorithm for structure-based drug design","volume":"35","author":"Fu","year":"2022","journal-title":"Adv Neural Inf Process Syst"},{"key":"2025042214235746800_btae730-B8","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.3390\/ijms20061375","article-title":"The light and dark sides of virtual screening: what is there to know?","volume":"20","author":"Gimeno","year":"2019","journal-title":"Int J Mol Sci"},{"key":"2025042214235746800_btae730-B9","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1109\/34.295910","article-title":"Simulated annealing: a proof of convergence","volume":"16","author":"Granville","year":"1994","journal-title":"IEEE Trans Pattern Anal Machine Intell"},{"key":"2025042214235746800_btae730-B10","author":"Guan"},{"key":"2025042214235746800_btae730-B11","author":"Guan"},{"key":"2025042214235746800_btae730-B12","doi-asserted-by":"crossref","first-page":"3086","DOI":"10.1016\/j.apsb.2024.01.019","article-title":"Deep simulated annealing for the discovery of novel dental anesthetics with local anesthesia and anti-inflammatory properties","volume":"14","author":"Hao","year":"2024","journal-title":"Acta Pharm Sin B"},{"key":"2025042214235746800_btae730-B13","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/prot.20512","article-title":"Binding MOAD (mother of all databases)","volume":"60","author":"Hu","year":"2005","journal-title":"Proteins: Struct Funct Bioinform"},{"key":"2025042214235746800_btae730-B14","author":"Huang"},{"key":"2025042214235746800_btae730-B15","doi-asserted-by":"crossref","first-page":"12671","DOI":"10.1609\/aaai.v38i11.29162","article-title":"Binding-adaptive diffusion models for structure-based drug design","volume":"38","author":"Huang","year":"2024","journal-title":"AAAI"},{"key":"2025042214235746800_btae730-B16","author":"Hwang","year":"1988"},{"key":"2025042214235746800_btae730-B17","doi-asserted-by":"crossref","first-page":"3567","DOI":"10.1039\/C8SC05372C","article-title":"A graph-based genetic algorithm and generative model\/Monte Carlo tree search for the exploration of chemical space","volume":"10","author":"Jensen","year":"2019","journal-title":"Chem Sci"},{"key":"2025042214235746800_btae730-B18","author":"Jin"},{"key":"2025042214235746800_btae730-B19","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with alphafold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"2025042214235746800_btae730-B20","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.addr.2012.09.019","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"64","author":"Lipinski","year":"2012","journal-title":"Adv Drug Deliv Rev"},{"key":"2025042214235746800_btae730-B21","author":"Liu"},{"key":"2025042214235746800_btae730-B22","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.neucom.2021.09.003","article-title":"Simulated annealing for optimization of graphs and sequences","volume":"465","author":"Liu","year":"2021","journal-title":"Neurocomputing"},{"key":"2025042214235746800_btae730-B23","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s44254-023-00047-x","article-title":"Anesthetic drug discovery with computer-aided drug design and machine learning","volume":"2","author":"Liu","year":"2024","journal-title":"APS"},{"key":"2025042214235746800_btae730-B24","first-page":"23894","article-title":"Zero-shot 3d drug design by sketching and generating","volume":"35","author":"Long","year":"2022","journal-title":"Adv Neural Inf Process Syst"},{"key":"2025042214235746800_btae730-B25","first-page":"6229","author":"Luo"},{"key":"2025042214235746800_btae730-B26","doi-asserted-by":"crossref","first-page":"2707","DOI":"10.1016\/j.drudis.2021.05.019","article-title":"De novo molecular design and generative models","volume":"26","author":"Meyers","year":"2021","journal-title":"Drug Discov Today"},{"key":"2025042214235746800_btae730-B27","author":"Nigam","year":"2020"},{"key":"2025042214235746800_btae730-B28","author":"Peng"},{"key":"2025042214235746800_btae730-B29","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1007\/s10822-013-9672-4","article-title":"Estimation of the size of drug-like chemical space based on gdb-17 data","volume":"27","author":"Polishchuk","year":"2013","journal-title":"J Comput Aided Mol Des"},{"key":"2025042214235746800_btae730-B30","doi-asserted-by":"crossref","first-page":"bbad435","DOI":"10.1093\/bib\/bbad435","article-title":"KGDIFF: towards explainable target-aware molecule generation with knowledge guidance","volume":"25","author":"Qian","year":"2023","journal-title":"Brief Bioinform"},{"key":"2025042214235746800_btae730-B31","author":"Qu"},{"key":"2025042214235746800_btae730-B32","doi-asserted-by":"crossref","first-page":"2701","DOI":"10.1039\/D1SC05976A","article-title":"Generating 3D molecules conditional on receptor binding sites with deep generative models","volume":"13","author":"Ragoza","year":"2022","journal-title":"Chem Sci"},{"key":"2025042214235746800_btae730-B33","author":"Schneuing","year":"2022"},{"key":"2025042214235746800_btae730-B34","doi-asserted-by":"crossref","first-page":"14360","DOI":"10.1021\/acsomega.9b02221","article-title":"Evolving concept of activity cliffs","volume":"4","author":"Stumpfe","year":"2019","journal-title":"ACS Omega"},{"key":"2025042214235746800_btae730-B35","doi-asserted-by":"crossref","first-page":"1003480","DOI":"10.3389\/fphar.2022.1003480","article-title":"Target-specific compound selectivity for multi-target drug discovery and repurposing","volume":"13","author":"Wang","year":"2022","journal-title":"Front Pharmacol"},{"key":"2025042214235746800_btae730-B36","author":"Xie"},{"key":"2025042214235746800_btae730-B37","author":"Xu"},{"key":"2025042214235746800_btae730-B38","author":"Yang","year":"2024"},{"key":"2025042214235746800_btae730-B39","author":"Zhang"},{"key":"2025042214235746800_btae730-B40","author":"Zhang"},{"key":"2025042214235746800_btae730-B41","author":"Zhou"},{"key":"2025042214235746800_btae730-B42","doi-asserted-by":"crossref","first-page":"10752","DOI":"10.1038\/s41598-019-47148-x","article-title":"Optimization of molecules via deep reinforcement learning","volume":"9","author":"Zhou","year":"2019","journal-title":"Sci Rep"},{"key":"2025042214235746800_btae730-B43","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.csbj.2020.11.052","article-title":"Advances in integrative structural biology: towards understanding protein complexes in their cellular context","volume":"19","author":"Ziegler","year":"2021","journal-title":"Comput Struct Biotechnol J"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btae730\/60951329\/btae730.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/41\/1\/btae730\/60951329\/btae730.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/41\/1\/btae730\/60951329\/btae730.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T18:24:06Z","timestamp":1745346246000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/doi\/10.1093\/bioinformatics\/btae730\/7916502"}},"subtitle":[],"editor":[{"given":"Arne","family":"Elofsson","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2024,12,4]]},"references-count":44,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,12,26]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btae730","relation":{},"ISSN":["1367-4811"],"issn-type":[{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,1]]},"published":{"date-parts":[[2024,12,4]]},"article-number":"btae730"}}