Flaviviral Protease Inhibitors Identified by Fragment-Based Library Docking into a Structure Generated by Molecular Dynamics
Flaviviral Protease Inhibitors Identified by Fragment-Based Library Docking into a Structure Generated by Molecular Dynamics
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DOI：
10.1021/jm900448m
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发表时间：
2009-08-13
影响因子：
7.3
通讯作者：
Caflisch, Amedeo
中科院分区：
文献类型：
--
作者：
Ekonomiuk, Dariusz;Su, Xun-Cheng;Caflisch, Amedeo
片段为基础的对接被用来选择一个虚拟筛选的构象从西尼罗病毒非结构3蛋白酶的分子动力学轨迹。这种构象是从100个分子动力学快照的集合中选择的，因为它最佳地容纳了苯，已知药物中最常见的环和两个带正电荷的片段（甲基胍和2-苯基咪唑啉）。后者的片段被用作探针，因为大量的氢键受体的底物结合位点的蛋白酶。在高通量对接的多样性集的18 694个分子和姿势过滤，只有五个化合物被选择用于实验验证，其中两个是活跃的在低微摩尔范围内的酶测定和色氨酸荧光猝灭测定。通过核磁共振光谱提供了与蛋白酶活性位点特异性结合的证据。这两种抑制剂具有不同的骨架（二苯基脲和二苯基酯），并且是有希望的主要候选物，因为它们具有约300 Da的分子量。
Fragment-based docking was used to select a conformation for virtual screening from a molecular dynamics trajectory of the West Nile virus nonstructural 3 protease. This conformation was chosen from an ensemble of 100 molecular dynamics snapshots because it optimally accommodates benzene, the most common ring in known drugs, and two positively charged fragments (methylguanidinium and 2-phenylimidazoline). The latter fragments were used as probes because of the large number of hydrogen bond acceptors in the substrate binding site of the protease. Upon high-throughput docking of a diversity set of 18 694 molecules and pose filtering, only five compounds were chosen for experimental validation, and two of them are active in the low micromolar range in an enzymatic assay and a tryptophan fluorescence quenching assay. Evidence for specific binding to the protease active site is provided by nuclear magnetic resonance spectroscopy. The two inhibitors have different scaffolds (diphenylurea and diphenyl ester) and are promising lead candidates because they have a molecular weight of about 300 Da.