Design and synthesis of potent HIV-1 protease inhibitors incorporating hydroxyprolinamides as novel P2 ligands |
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Authors: | Gao Bing-Lei Zhang Cheng-Mei Yin Yi-Zhen Tang Long-Qian Liu Zhao-Peng |
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Institution: | School of Pharmaceutical Sciences, Shandong University, No. 44 Wenhua Xilu, Jinan 250012, Shandong Province, PR China |
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Abstract: | A series of new HIV-1 protease inhibitors with the hydroxyethylamine core and different hydroxyprolinamide P2 ligands were designed and synthesized. Variation of substitutions at the P2 significantly affected the enzyme inhibitory potency of the inhibitors. Compounds 2a and 2d showed excellent enzyme inhibitory activity with IC50 values in the nanomolar range. An active site binding model for inhibitors 2a and 2d was suggested based upon the computational-docking results of the ligand with HIV-1 protease. This model offers molecular insights regarding ligand-binding site interactions of the hydroxyprolinamide-derived novel P2-ligand. |
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Keywords: | HIV-1 protease inhibitors Hydroxyprolinamide P2 ligand Drug-resistant Design Synthesis |
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