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In the process of novel multi-target drugs (MTDs) discovery, in silico strategies come to be quite essential for the advantage of high throughput and low cost. However, current researchers mostly aim at typical closely related target pairs. Because of the intricate pathogenesis networks of complex diseases, many distantly related targets are found to play crucial role in synergistic treatment. Therefore, an innovational method to develop drugs which could simultaneously target distantly related target pairs is of utmost importance. At the same time, reducing the false discovery rate in the design of MTDs remains to be the daunting technological difficulty. In this research, effective small molecule clustering in the positive dataset, together with a putative negative dataset generation strategy, was adopted in the process of model constructions. Through comprehensive assessment on 10 target pairs with hierarchical similarity-levels, the proposed strategy turned out to reduce the false discovery rate successfully. Constructed model types with much smaller numbers of inhibitor molecules gained considerable yields and showed better false-hit controllability than before. To further evaluate the generalization ability, an in-depth assessment of high-throughput virtual screening on ChEMBL database was conducted. As a result, this novel strategy could hierarchically improve the enrichment factors for each target pair (especially for those distantly related\/unrelated target pairs), corresponding to target pair similarity-levels.<\/jats:p>","DOI":"10.1093\/bib\/bbac621","type":"journal-article","created":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T03:06:36Z","timestamp":1673492796000},"source":"Crossref","is-referenced-by-count":11,"title":["A novel strategy for designing the magic shotguns for distantly related target pairs"],"prefix":"10.1093","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4140-5392","authenticated-orcid":false,"given":"Yongchao","family":"Luo","sequence":"first","affiliation":[{"name":"Zhejiang University College of Pharmaceutical Sciences, , Hangzhou 310058 , China"}]},{"given":"Panpan","family":"Wang","sequence":"additional","affiliation":[{"name":"Huanghuai University College of Chemistry and Pharmaceutical Engineering, , Zhumadian 463000 , China"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7619-2975","authenticated-orcid":false,"given":"Minjie","family":"Mou","sequence":"additional","affiliation":[{"name":"Zhejiang University College of Pharmaceutical Sciences, , Hangzhou 310058 , China"}]},{"given":"Hanqi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Zhejiang University College of Pharmaceutical Sciences, , Hangzhou 310058 , China"}]},{"given":"Jiajun","family":"Hong","sequence":"additional","affiliation":[{"name":"Zhejiang University College of Pharmaceutical Sciences, , Hangzhou 310058 , China"}]},{"given":"Lin","family":"Tao","sequence":"additional","affiliation":[{"name":"Hangzhou Normal University Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, School of Medicine, , Hangzhou 310036 , China"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8069-0053","authenticated-orcid":false,"given":"Feng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Zhejiang University College of Pharmaceutical Sciences, , Hangzhou 310058 , China"}]}],"member":"286","published-online":{"date-parts":[[2023,1,11]]},"reference":[{"key":"2023011917113391100_ref1","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/s41592-021-01126-2","article-title":"A versatile polypharmacology platform promotes cytoprotection and viability of human pluripotent and differentiated cells","volume":"18","author":"Chen","year":"2021","journal-title":"Nat Methods"},{"key":"2023011917113391100_ref2","first-page":"1153","article-title":"In silico polypharmacology of natural products","volume":"19","author":"Fang","year":"2018","journal-title":"Brief Bioinform"},{"key":"2023011917113391100_ref3","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/978-1-4939-8630-9_13","article-title":"Exploring polypharmacology in drug design","volume":"1824","author":"Saenz-Mendez","year":"2018","journal-title":"Methods Mol 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