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Spt5 was also recognized for its roles in the transcription of expanded-repeat genes that are related to neurodegenerative diseases. Recently, a set of Spt5-Pol II small molecule inhibitors (SPIs) were reported, which selectively inhibit mutant huntingtin gene transcription. Inhibition mechanisms as well as interaction sites of these SPIs with Pol II and Spt5 are not entirely known. In this study, we predicted the binding sites of three selected SPIs at the Pol II-Spt5 interface by docking and molecular dynamics simulations. Two molecules out of three demonstrated strong binding with Spt5 and Pol II, while the other molecule was more loosely bound and sampled multiple binding sites. Strongly bound SPIs indirectly affected RNA and DNA dynamics at the exit site as DNA became more flexible while RNA was stabilized by increased interactions with Spt5. Our results suggest that the transcription inhibition mechanism induced by SPIs can be related to Spt5-nucleic acid interactions, which were altered to some extent with strong binding of SPIs.<\/jats:p>","DOI":"10.1007\/s10822-023-00543-z","type":"journal-article","created":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T03:06:45Z","timestamp":1700536005000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Binding of small molecule inhibitors to RNA polymerase-Spt5 complex impacts RNA and DNA stability"],"prefix":"10.1007","volume":"38","author":[{"given":"Adan","family":"Gallardo","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0333-5757","authenticated-orcid":false,"given":"Bercem","family":"Dutagaci","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,11,21]]},"reference":[{"key":"543_CR1","doi-asserted-by":"publisher","first-page":"15972","DOI":"10.1002\/anie.201608066","volume":"55","author":"M Hantsche","year":"2016","unstructured":"Hantsche M, Cramer P (2016) The structural basis of transcription: 10 years after the Nobel Prize in chemistry. 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