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inhibitor (INSTI) for HIV treatment and prevention. Cabotegravir-based long-acting pre-exposure prophylaxis (PrEP) presents an emerging paradigm for infectious disease control. In this scheme, a combination of a high efficacy and low solubility of anti-infection drugs permits the establishment of a pharmaceutical firewall in HIV-vulnerable groups over a long period. Although the structure-activity-relationship (SAR) of cabotegravir as an INSTI is known, the structural determinants of its low solubility have not been identified. In this work, we have integrated multiple experimental and computational methods, namely X-ray diffraction, solid-state NMR (SSNMR) spectroscopy, solution NMR spectroscopy, automated fragmentation (AF)-QM\/MM and density functional theory (DFT) calculations, to address this question. The molecular organization of cabotegravir in crystal lattice has been determined. The combination of very-fast magic-angle-sample-spinning (VF MAS) SSNMR and solution NMR, as supported by AF-QM\/MM and DFT calculations, permits the identification of structural factors that contribute to the low aqueous solubility of cabotegravir. Our study reveals the multitasking nature of pharmacophores in cabotegravir, which controls the drug solubility and, meanwhile, the biological activity. By unraveling these function-defining molecular features, our work could inspire further development of long-acting HIV PrEP drugs.<\/jats:p>","DOI":"10.3390\/molecules29020376","type":"journal-article","created":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T12:56:33Z","timestamp":1704977793000},"page":"376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Multitasking Pharmacophores Support Cabotegravir-Based Long-Acting HIV Pre-Exposure Prophylaxis (PrEP)"],"prefix":"10.3390","volume":"29","author":[{"given":"Zheng","family":"Wan","sequence":"first","affiliation":[{"name":"Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Frontiers Science Center of Molecule Intelligent Syntheses, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Shi","sequence":"additional","affiliation":[{"name":"Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Frontiers Science Center of Molecule Intelligent Syntheses, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqing","family":"Gong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5609-9749","authenticated-orcid":false,"given":"Massimo","family":"Lucci","sequence":"additional","affiliation":[{"name":"C.I.R.M.M.P.\u2014Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine, Via L. 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