Design, synthesis and evaluation of novel HIV-1 NNRTIs with dual structural conformations targeting the entrance channel of the NNRTI binding pocket
Design, synthesis and evaluation of novel HIV-1 NNRTIs with dual structural conformations targeting the entrance channel of the NNRTI binding pocket
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设计、合成和评估具有双重结构构象的新型 HIV-1 NNRTI，靶向 NNRTI 结合袋的入口通道。
DOI：
10.1016/j.ejmech.2016.02.068
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发表时间：
2016-06-10
影响因子：
6.7
通讯作者：
Liu, Xinyong
中科院分区：
文献类型：
--
作者：
Meng, Qing;Chen, Xuwang;Liu, Xinyong
基于结构生物电子等排置换和分子杂交策略，设计并合成了一系列针对HIV-1 NNRTI结合口袋（NNIBP）“入口通道”的新型双构-构象抑制剂。用MTT法测定了所有化合物在MT-4细胞中的抗HIV活性。5种化合物显示出中等至优异的抑制野生型（wt）HIV-1复制的效力，EC 50值范围为31.36 μ M至0.11 μ M。其中，化合物15 b被鉴定为最有效的抑制剂，其对wt和K103 N/Y181 C双突变HIV-1株（RES 056）的EC 50值分别为Oil μ M和2.18 μ M。此外，初步的构效关系（SAR）和分子模拟研究进行了讨论，这可能会提供有价值的见解，为进一步优化。(C)2016 Elsevier Masson SAS。All rights reserved.
On the basis of structure-based bioisosteric replacement and molecular hybridization strategy, a series of novel dual structural-conformation inhibitors targeting the "entrance channel" of HIV-1 NNRTIs binding pocket (NNIBP) were designed and synthesized. All of the new compounds were evaluated for their anti HIV activities in MT-4 cells using the MTT method. Five compounds exhibited moderate to excellent potencies inhibiting wild-type (wt) HIV-1 replication with EC50 values ranging from 31.36 mu M to 0.11 mu M. Among them, compound 15b was identified as the most potent inhibitor with EC50 values of Oil mu M and 2.18 mu M against wt and K103N/Y181C double mutant HIV-1 strain (RES056), respectively. In addition, preliminary structure activity relationships (SARs) and molecular simulation studies were discussed, which may provide valuable insights for further optimization. (C) 2016 Elsevier Masson SAS. All rights reserved.