2. Academic Validation
  3. Identification of novel potent HIV-1 inhibitors by exploiting the tolerant regions of the NNRTIs binding pocket

Identification of novel potent HIV-1 inhibitors by exploiting the tolerant regions of the NNRTIs binding pocket

  • Eur J Med Chem. 2021 Mar 15:214:113204. doi: 10.1016/j.ejmech.2021.113204.
Yanying Sun 1,  Dongwei Kang 2,  Feng Da 1,  Tao Zhang 1,  Pei Li 3,  Baodan Zhang 3,  Erik De Clercq 4,  Christophe Pannecouque 4,  Peng Zhan 5,  Xinyong Liu 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
  • 2 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China; Suzhou Research Institute, Shandong University, Room522, Building H of NUSP, NO.388 Ruoshui Road, SIP, Suzhou, 215123 Jiangsu, PR China. Electronic address: kangdongwei@sdu.edu.cn.
  • 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
  • 4 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium.
  • 5 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address: zhanpeng1982@163.com.
  • 6 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 33567378 DOI: 10.1016/j.ejmech.2021.113204
Abstract

With our previously identified potent NNRTIs 25a and HBS-11c as leads, series of novel thiophene[3,2-d]pyrimidine and thiophene[2,3-d]pyrimidine derivatives were designed via molecular hybridization strategy. All the target compounds were evaluated for their anti-HIV-1 activity and cytotoxicity in MT-4 cells. Compounds 16a1 and 16b1 turned out to be the most potent inhibitors against WT and mutant HIV-1 strains (L100I, K103N, and E138K), with EC50 values ranging from 0.007 μM to 0.043 μM. Gratifyingly, 16b1 exhibited significantly reduced cytotoxicity (CC50 > 217.5 μM) and improved water solubility (S = 49.3 μg/mL at pH 7.0) compared to the lead 25a (S < 1 μg/mL at pH 7.0, CC50 = 2.30 μM). Moreover, molecular docking was also conducted to rationalize the structure-activity relationships of these novel derivatives and to understand their key interactions with the binding pocket.

Keywords

DAPY; HIV-1; NNIBP; NNRTIs; Tolerant regions.

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