{"title":"作为 HIV-1 蛋白酶抑制剂的 Darunavir 类似物的设计、合成和生物学评价","authors":"Muhammad Asad Ur Rehman, Hathaichanok Chuntakaruk, Soraat Amphan, Aphinya Suroengrit, Kowit Hengphasatporn, Yasuteru Shigeta, Thanyada Rungrotmongkol, Kuakarun Krusong, Siwaporn Boonyasuppayakorn, Chanat Aonbangkhen, Tanatorn Khotavivattana","doi":"10.1021/acsbiomedchemau.4c00040","DOIUrl":null,"url":null,"abstract":"Darunavir, a frontline treatment for HIV infection, faces limitations due to emerging multidrug resistant (MDR) HIV strains, necessitating the development of analogs with improved activity. In this study, a combinatorial in silico approach was used to initially design a series of HIV-1 PI analogs with modifications at key sites, P1′ and P2′, to enhance interactions with HIV-1 PR. Fifteen analogs with promising binding scores were selected for synthesis and evaluated for the HIV-1 PR inhibition activity. The variation of P2′ substitution was found to be effective, as seen in <b>5aa</b> (1.54 nM), <b>5ad</b> (0.71 nM), <b>5ac</b> (0.31 nM), <b>5ae</b> (0.28 nM), and <b>5af</b> (1.12 nM), featuring halogen, aliphatic, and alkoxy functionalities on the phenyl sulfoxide motif exhibited superior inhibition against HIV-1 PR compared to DRV, with minimal cytotoxicity observed in Vero and 293T cell lines. Moreover, computational studies demonstrated the potential of selected analogs to inhibit various HIV-1 PR mutations, including I54M and I84V. Further structural dynamics and energetic analyses confirmed the stability and binding affinity of promising analogs, particularly <b>5ae</b>, which showed strong interactions with key residues in HIV-1 PR. Overall, this study underscores the importance of flexible moieties and interaction enhancement at the S2′ subsite of HIV-1 PR in developing effective DRV analogs to combat HIV and other global health issues.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":null,"pages":null},"PeriodicalIF":3.8000,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Design, Synthesis, and Biological Evaluation of Darunavir Analogs as HIV-1 Protease Inhibitors\",\"authors\":\"Muhammad Asad Ur Rehman, Hathaichanok Chuntakaruk, Soraat Amphan, Aphinya Suroengrit, Kowit Hengphasatporn, Yasuteru Shigeta, Thanyada Rungrotmongkol, Kuakarun Krusong, Siwaporn Boonyasuppayakorn, Chanat Aonbangkhen, Tanatorn Khotavivattana\",\"doi\":\"10.1021/acsbiomedchemau.4c00040\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Darunavir, a frontline treatment for HIV infection, faces limitations due to emerging multidrug resistant (MDR) HIV strains, necessitating the development of analogs with improved activity. In this study, a combinatorial in silico approach was used to initially design a series of HIV-1 PI analogs with modifications at key sites, P1′ and P2′, to enhance interactions with HIV-1 PR. Fifteen analogs with promising binding scores were selected for synthesis and evaluated for the HIV-1 PR inhibition activity. The variation of P2′ substitution was found to be effective, as seen in <b>5aa</b> (1.54 nM), <b>5ad</b> (0.71 nM), <b>5ac</b> (0.31 nM), <b>5ae</b> (0.28 nM), and <b>5af</b> (1.12 nM), featuring halogen, aliphatic, and alkoxy functionalities on the phenyl sulfoxide motif exhibited superior inhibition against HIV-1 PR compared to DRV, with minimal cytotoxicity observed in Vero and 293T cell lines. Moreover, computational studies demonstrated the potential of selected analogs to inhibit various HIV-1 PR mutations, including I54M and I84V. Further structural dynamics and energetic analyses confirmed the stability and binding affinity of promising analogs, particularly <b>5ae</b>, which showed strong interactions with key residues in HIV-1 PR. Overall, this study underscores the importance of flexible moieties and interaction enhancement at the S2′ subsite of HIV-1 PR in developing effective DRV analogs to combat HIV and other global health issues.\",\"PeriodicalId\":29802,\"journal\":{\"name\":\"ACS Bio & Med Chem Au\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2024-09-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Bio & Med Chem Au\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1021/acsbiomedchemau.4c00040\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Bio & Med Chem Au","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1021/acsbiomedchemau.4c00040","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Design, Synthesis, and Biological Evaluation of Darunavir Analogs as HIV-1 Protease Inhibitors
Darunavir, a frontline treatment for HIV infection, faces limitations due to emerging multidrug resistant (MDR) HIV strains, necessitating the development of analogs with improved activity. In this study, a combinatorial in silico approach was used to initially design a series of HIV-1 PI analogs with modifications at key sites, P1′ and P2′, to enhance interactions with HIV-1 PR. Fifteen analogs with promising binding scores were selected for synthesis and evaluated for the HIV-1 PR inhibition activity. The variation of P2′ substitution was found to be effective, as seen in 5aa (1.54 nM), 5ad (0.71 nM), 5ac (0.31 nM), 5ae (0.28 nM), and 5af (1.12 nM), featuring halogen, aliphatic, and alkoxy functionalities on the phenyl sulfoxide motif exhibited superior inhibition against HIV-1 PR compared to DRV, with minimal cytotoxicity observed in Vero and 293T cell lines. Moreover, computational studies demonstrated the potential of selected analogs to inhibit various HIV-1 PR mutations, including I54M and I84V. Further structural dynamics and energetic analyses confirmed the stability and binding affinity of promising analogs, particularly 5ae, which showed strong interactions with key residues in HIV-1 PR. Overall, this study underscores the importance of flexible moieties and interaction enhancement at the S2′ subsite of HIV-1 PR in developing effective DRV analogs to combat HIV and other global health issues.
期刊介绍:
ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.