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However, similar to other clinically used antiviral drugs, resistance-causing mutations have appeared, which have impaired the efficacy of INSTIs. In the current study, to identify novel integrase inhibitors, a set of molecular docking-based virtual screenings were performed, and indole-2-carboxylic acid was developed as a potent INSTI scaffold. Indole-2-carboxylic acid derivative 3 was proved to effectively inhibit the strand transfer of HIV-1 integrase, and binding conformation analysis showed that the indole core and C2 carboxyl group obviously chelated the two Mg2+ ions within the active site of integrase. Further structural optimizations on compound 3 provided the derivative 20a, which markedly increased the integrase inhibitory effect, with an IC50 value of 0.13 \u03bcM. Binding mode analysis revealed that the introduction of a long branch on C3 of the indole core improved the interaction with the hydrophobic cavity near the active site of integrase, indicating that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.<\/jats:p>","DOI":"10.3390\/molecules28248020","type":"journal-article","created":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T14:12:51Z","timestamp":1702303971000},"page":"8020","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Discovery of Indole-2-carboxylic Acid Derivatives as Novel HIV-1 Integrase Strand Transfer Inhibitors"],"prefix":"10.3390","volume":"28","author":[{"given":"Yu-Chan","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang 550004, China"},{"name":"Center for Tissue Engineering and Stem Cell Research, Key Laboratory of Regenerative Medicine of Guizhou Province, School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550004, China"},{"name":"School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang 550025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang 550004, China"},{"name":"School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang 550025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong-Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang 550004, China"},{"name":"Center for Tissue Engineering and Stem Cell Research, Key Laboratory of Regenerative Medicine of Guizhou Province, School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun-Hua","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang 550004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong-Long","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang 550025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo-Yi","family":"Yan","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Xinxiang University, Xinxiang 453000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shang-Gao","family":"Liao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang 550025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0479-6259","authenticated-orcid":false,"given":"Yong-Jun","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang 550004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang 550004, China"},{"name":"School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang 550025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.jiac.2016.10.002","article-title":"Current status of HIV\/AIDS in the ART era","volume":"23","author":"Yoshimura","year":"2017","journal-title":"J. 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