The pathogen Legionella longbeachae is a causative agent of legionellosis. The antibiotic resistance is the major problem of this modern world. Thus, selective pressure warrants the need for identification of newer drug target. In current study, subtractive proteomics approach screen out SIS (sugar isomerase) domain protein as an attractive receptor molecule for rational drug design. This protein is involved in lipopolysaccharide biosynthesis and catalyzes the isomerization of sedoheptulose 7-phosphate in d-glycero-d-manno-heptose 7-phosphate. Molecular docking revealed compound 1 (2-(6-(N,N-dimethyl sulfamoyl)pipridin-4-yl)pyrazin-2-yl)imidazol-3-ium-1-ide) as the potent inhibitor having GOLD fitness score of 69. The complex is affirmed by half-site effect via simulation analysis. Complex stability was investigated via several approaches that follows dynamic simulation and binding energies. Trajectory analysis revealed slight change in ring positioning of inhibitor inside the active pocket during 130 ns (nanosecond). Interestingly, it was affirmed via binding interactions’ density distribution. Hence, radial distribution function (RDF) inferred that SER55 and SER83 are the major residues that take part in hydrogen bonding and complex stability. Furthermore, an indigenously developed method axial frequency distribution (AFD) has revealed that ligand moved closer to the active site with both the residues SER55 and SER83 binding to the ligand. The phenomena was observed via rotating motion with respect to receptor center cavity. Thus, inhibitor movement towards allosteric site was observed at the end of simulations. Finally, binding free energy calculations by MMPB/GBSA predicts high compound affinity for the complex. Hence, findings from the current study will aid in the novel drug discovery and future experimental studies.

Graphical abstract

中文翻译：

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深入了解天然抑制剂，并桥接到针对糖异构酶（SIS）域蛋白的动态模拟。

长病菌退伍军人病菌是军团菌病的病原体。抗生素抗性是这个现代世界的主要问题。因此，选择性压力保证了需要鉴定较新的药物靶标。在当前的研究中，减蛋白质组学方法筛选出SIS（糖异构酶）域蛋白作为合理的药物设计中有吸引力的受体分子。此蛋白参与脂多糖生物合成和催化景天庚酮糖-7-磷酸中的异构化d -glycero- d -manno-庚糖-7-磷酸。分子对接揭示化合物1（2-（6-（6-（N，N-二甲基氨磺酰基）哌丁啶-4-基）吡嗪-2-基）咪唑-3-基-1-ide）为GOLD适应性得分为69的有效抑制剂。通过仿真分析得到了半现场效应的肯定。通过遵循动态模拟和结合能的几种方法研究了复杂的稳定性。轨迹分析表明，在130 ns（纳秒）内，抑制剂在活性囊内部的环位置略有变化。有趣的是，它是通过结合相互作用的密度分布得到证实的。因此，径向分布函数（RDF）推断SER55和SER83是参与氢键和复杂稳定性的主要残基。此外，一种本地开发的方法轴向频率分布（AFD）已显示，配体通过残基SER55和SER83均与配体结合，从而更靠近活性位点。通过相对于受体中心腔的旋转运动观察到该现象。因此，在模拟结束时观察到抑制剂向变构位点移动。最后，通过MMPB / GBSA的结合自由能计算可预测该化合物对复合物的亲和力高。因此，当前研究的结果将有助于新药的发现和未来的实验研究。MMPB / GBSA的结合自由能计算可预测该复合物的高化合物亲和力。因此，当前研究的结果将有助于新药的发现和未来的实验研究。MMPB / GBSA的结合自由能计算可预测该复合物的高化合物亲和力。因此，本研究的发现将有助于新药的发现和未来的实验研究。

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