2. Academic Validation
  3. Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays

Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays

  • Bioorg Med Chem. 2017 Aug 15;25(16):4397-4406. doi: 10.1016/j.bmc.2017.06.022.
Boshi Huang 1,  Xueshun Wang 1,  Xinhao Liu 1,  Zihui Chen 1,  Wanzhuo Li 1,  Songkai Sun 1,  Huiqing Liu 2,  Dirk Daelemans 3,  Erik De Clercq 3,  Christophe Pannecouque 3,  Peng Zhan 4,  Xinyong Liu 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.
  • 2 Department of Pharmacology, School of Medicine, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.
  • 3 Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
  • 4 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
  • 5 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 28659246 DOI: 10.1016/j.bmc.2017.06.022
Abstract

Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC50 values of 1.48μM and 1.61μM, respectively. They were much potent than the reference drug ddI (EC50=76.0μM) and comparable to 3TC (EC50=2.54μM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed.

Keywords

Crystallographic overlays; DAPY-IAS hybrids; Drug design; HIV-1 inhibitors; Molecular modeling; SARs.

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