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Here we present complementary data-driven algorithms to minimize the search in chemical space for phenylthiazole-containing molecules that bind the RNA hairpin within the ribosomal peptidyl transferase center (PTC) of<jats:italic>Mycobacterium tuberculosis<\/jats:italic>. Our results indicate visual, geometrical, and chemical features that enhance the binding to the targeted RNA. Functional validation was conducted after synthesizing 10 small molecules pinpointed computationally. Four of the 10 were found to be potent inhibitors that target hairpin 91 in the ribosomal PTC of<jats:italic>M. tuberculosis<\/jats:italic>and, as a result, stop translation.<\/jats:p><jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>","DOI":"10.1186\/s13321-022-00583-x","type":"journal-article","created":{"date-parts":[[2022,2,2]],"date-time":"2022-02-02T20:53:52Z","timestamp":1643835232000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Machine learning approaches to optimize small-molecule inhibitors for RNA targeting"],"prefix":"10.1186","volume":"14","author":[{"given":"Hadar","family":"Grimberg","sequence":"first","affiliation":[]},{"given":"Vinay S.","family":"Tiwari","sequence":"additional","affiliation":[]},{"given":"Benjamin","family":"Tam","sequence":"additional","affiliation":[]},{"given":"Lihi","family":"Gur-Arie","sequence":"additional","affiliation":[]},{"given":"Daniela","family":"Gingold","sequence":"additional","affiliation":[]},{"given":"Lea","family":"Polachek","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3882-2742","authenticated-orcid":false,"given":"Barak","family":"Akabayov","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2022,2,2]]},"reference":[{"key":"583_CR1","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.1021\/ja02231a009","volume":"41","author":"I Langmuir","year":"1919","unstructured":"Langmuir I (1919) Isomorphism, isosterism and covalence. 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