{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:51:30Z","timestamp":1760143890344,"version":"build-2065373602"},"reference-count":36,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T00:00:00Z","timestamp":1709164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273909"],"award-info":[{"award-number":["82273909"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The \u03b12A adrenergic receptor (\u03b12A-AR) serves as a critical molecular target for sedatives and analgesics. However, \u03b12A-AR ligands with an imidazole ring also interact with an imidazoline receptor as well as other proteins and lead to undesirable effects, motivating us to develop more novel scaffold \u03b12A-AR ligands. For this purpose, we employed an ensemble-based ligand discovery strategy, integrating long-term molecular dynamics (MD) simulations and virtual screening, to identify new potential \u03b12A-AR agonists with novel scaffold. Our results showed that compounds SY-15 and SY-17 exhibited significant biological effects in the preliminary evaluation of protein kinase A (PKA) redistribution assays. They also reduced levels of intracellular cyclic adenosine monophosphate (cAMP) in a dose-dependent manner. Upon treatment of the cells with 100 \u03bcM concentrations of SY-15 and SY-17, there was a respective decrease in the intracellular cAMP levels by 63.43% and 53.83%. Subsequent computational analysis was conducted to elucidate the binding interactions of SY-15 and SY-17 with the \u03b12A-AR. The binding free energies of SY-15 and SY-17 calculated by MD simulations were \u221245.93 and \u221271.97 kcal\/mol. MD simulations also revealed that both compounds act as bitopic agonists, occupying the orthosteric site and a novel exosite of the receptor simultaneously. Our findings of integrative computational and experimental approaches could offer the potential to enhance ligand affinity and selectivity through dual-site occupancy and provide a novel direction for the rational design of sedatives and analgesics.<\/jats:p>","DOI":"10.3390\/molecules29051097","type":"journal-article","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T03:31:23Z","timestamp":1709263883000},"page":"1097","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel Scaffold Agonists of the \u03b12A Adrenergic Receptor Identified via Ensemble-Based Strategy"],"prefix":"10.3390","volume":"29","author":[{"given":"Shiyang","family":"Sun","sequence":"first","affiliation":[{"name":"National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1592-6554","authenticated-orcid":false,"given":"Pengyun","family":"Li","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaqi","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongsheng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingting","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peilan","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruibin","family":"Su","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhibing","family":"Zheng","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Song","family":"Li","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2478781","DOI":"10.1155\/2020\/2478781","article-title":"\u03b1 (2)-Adrenoceptors: Challenges and Opportunities-Enlightenment from the Kidney","volume":"2020","author":"Pettinger","year":"2020","journal-title":"Cardiovasc. 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