期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 23, 期 24, 页码 6593-6597出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.10.059
关键词
HIV-1 NNRTIs; DAPY; Piperidin-4-yl-aminopyrimidines; Dual conformations; Molecular hybridization
资金
- National Natural Science Foundation of China (NSFC) [81273354, 81102320, 30873133, 30772629, 30371686]
- Key Project of NSFC for International Cooperation [30910103908]
- Research Fund for the Doctoral Program of Higher Education of China [20110131130005, 20110131120037]
- Natural Science Foundation of Shandong province [ZR2009CM016]
- Independent Innovation Foundation of Shandong University (IIFSDU) [2010GN044]
- Shandong Postdoctoral Innovation Science Research Special Program [201002023]
- China Postdoctoral Science Foundation [20100481282, 2012T50584]
- KU Leuven [GOA 10/014]
A series of novel piperidinylamino-diarylpyrimidine (pDAPY) derivatives with dual structural conformations was designed through a molecular hybridization strategy and expected to bind into the non-nucleoside inhibitor binding pocket (NNIBP) of HIV-1 RT in a flexible manner. A cell-based antiviral screening assay showed that some compounds were active against both wild-type and drug-resistant mutant virus strains (K103N+Y181C RT) of HIV-1 (compound 10b3 with EC50 = 0.047 and 4.6 mu M, selectivity index = 2145 and 22, respectively). Molecular simulation studies indicated that compound 10b3 could maintain the key hydrophobic interaction and hydrogen bonds with the NNIBP of two RT/ligand complexes. In particular, it could simultaneously occupy the protein/solvent interface and the entrance channel. Exploring these hybrid molecules with dual binding conformations might provide optional chemical scaffolds as novel HIV-1 reverse transcriptase inhibitors (HIV-1 NNRTIs). (C) 2013 Elsevier Ltd. All rights reserved.
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