Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary.
Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary.
Bioorg Med Chem. 2019 Apr 15;27(8):1497-1508. doi: 10.1016/j.bmc.2019.02.029. Epub 2019 Feb 16.
Structure based optimization of B39, an indazole-based low micromolar JAK2 virtual screening hit is reported. Analysing the effect of certain modifications on the activity and selectivity of the analogues suggested that these parameters are influenced by water molecules available in the binding site. Simulation of water networks in combination with docking enabled us to identify the key waters and to optimize our primary hit into a low nanomolar JAK2 lead with promising selectivity over JAK1.
报道了一种基于吲唑的低微摩尔 JAK2 虚拟筛选命中物 B39 的基于结构的优化。分析某些修饰对类似物活性和选择性的影响表明，这些参数受结合位点中可用水分子的影响。结合对接模拟水网络使我们能够识别关键的水分子，并将我们的初步命中物优化为具有良好 JAK1 选择性的低纳摩尔 JAK2 先导化合物。
