Laboratoire de Chimie Biologique Structurale (CBS), Namur Medicine and Drug Innovation Center (NAMEDIC), Namur Research Institute for Life Sciences (NARILIS), University of Namur (UNamur), B-5000 Namur, Belgium.
Tuberculosis Research Laboratory, Translational Health Science and Technology Institute, Faridabad 121001, Haryana, India.
Molecules. 2020 Jan 19;25(2):415. doi: 10.3390/molecules25020415.
is still the deadliest bacterial pathogen worldwide and the increasing number of multidrug-resistant tuberculosis cases further complicates this global health issue. phosphoserine phosphatase SerB2 is a promising target for drug design. Besides being a key essential metabolic enzyme of the pathogen's serine pathway, it appears to be involved in immune evasion mechanisms. In this work, a malachite green-based phosphatase assay has been used to screen 122 compounds from an internal chemolibrary. Trisubstituted harmine derivatives were found among the best hits that inhibited SerB2 activity. Synthesis of an original compound helped to discuss a brief structure activity relationship evaluation. Kinetics experiments showed that the most potent derivatives inhibit the phosphatase in a parabolic competitive fashion with apparent inhibition constants ( K i ) values in the micromolar range. Their interaction modes with the enzyme were investigated through induced fit docking experiments, leading to results consistent with the experimental data. Cellular assays showed that the selected compounds also inhibited growth in vitro. Those promising results may provide a basis for the development of new antimycobacterial agents targeting SerB2.
结核分枝杆菌仍然是全球最致命的细菌病原体，越来越多的耐多药结核病病例使这一全球健康问题更加复杂。磷酸丝氨酸磷酸酶 SerB2 是药物设计的一个有前途的靶点。它不仅是病原体丝氨酸途径的关键必需代谢酶，似乎还参与免疫逃避机制。在这项工作中，使用孔雀石绿为基础的磷酸酶检测法从内部化学文库中筛选了 122 种化合物。三取代哈尔明衍生物是抑制 SerB2 活性的最佳抑制剂之一。合成一种原始化合物有助于对简要的构效关系评价进行讨论。动力学实验表明，最有效的衍生物以抛物线竞争的方式抑制磷酸酶，表观抑制常数（ K i ）值在微摩尔范围内。通过诱导契合对接实验研究了它们与酶的相互作用模式，得到的结果与实验数据一致。细胞实验表明，所选化合物也能抑制 体外生长。这些有希望的结果可能为开发针对 SerB2 的新型抗分枝杆菌药物提供基础。
