Here we report a theoretical-experimental study of 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine derivatives that act as inhibitors of bacterial DNA gyrase B (GyrB). A comprehensive analysis of the various molecular interactions that stabilize the molecular complexes was performed using combined theoretical techniques. Our results showed that QTAIM (Quantum Theory of Atoms In Molecules) calculations are a very useful tool for quantitatively describing the molecular interactions to determine which amino acids interact with the ligands. Moreover, our simulations have shown that this approach not only provides a detailed description of the different affinities of the ligands, but also has predictive power for compounds that have not yet been synthesized. In fact, we have synthesized and tested three new DNA gyrase inhibitors, two of which exhibit significant inhibitory activity. One of them binds spatially differently from known GyrB inhibitors because its 3-oxopropanoic acid moiety is oriented toward a previously unexplored subsite of the binding pocket.

中文翻译：

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基于计算机辅助结构的优化 4,5,6,7-四氢苯并[d]噻唑-2,6-二胺衍生物作为 DNA 促旋酶 B 抑制剂

在这里，我们报告了 4,5,6,7-四氢苯并[ d的理论-实验研究]噻唑-2,6-二胺衍生物，可作为细菌 DNA 促旋酶 B (GyrB) 的抑制剂。使用组合理论技术对稳定分子复合物的各种分子相互作用进行了综合分析。我们的结果表明，QTAIM（分子中原子的量子理论）计算是一种非常有用的工具，可用于定量描述分子相互作用以确定哪些氨基酸与配体相互作用。此外，我们的模拟表明，这种方法不仅提供了对配体不同亲和力的详细描述，而且对尚未合成的化合物具有预测能力。事实上，我们已经合成并测试了三种新的 DNA 促旋酶抑制剂，其中两种表现出显着的抑制活性。