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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >From normal to competo-allosteric regulation: insights into the binding pattern dynamics of DSPI protein of Pseudomonas aeruginosa
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From normal to competo-allosteric regulation: insights into the binding pattern dynamics of DSPI protein of Pseudomonas aeruginosa

机译:从正常到竞争对手的分析规则:洞察铜绿假单胞菌DSPI蛋白的结合模式动态见解

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DSPI, a putative enoyl-coenzyme A (CoA) hydratase/isomerase, is anticipated to be involved in the synthesis of cis-2-decenoic acid (CDA), a quorum sensing (QS) signal molecule present in the superbug Pseudomonas aeruginosa. The current study not only adapts a broad-spectrum strategy for the lucid design of small molecule modulators but also provides novel allosteric inhibitors for DSPI, to investigate its function and potential as a therapeutic target. Docking analysis revealed that the compound 10252273, bound to the specific allosteric site, interacted with Glu118, unique amino acid residue of the active binding pocket, hence indicates the presence of a competitive allosteric site. The current study thus identifies and characterizes inhibitors by targeting the normal binding site and also reports the presence of the competo-allosteric site in the same binding tunnel as the normal site. Molecular docking studies proposed two chemical compounds that share a benzamide-benzimidazole (BB) backbone as potent inhibitors that can obstruct the mechanism of DSPI by targeting both the normal and proposed allosteric binding sites. MD simulations further revealed the disruption of the normal binding site due to the displacement of critical residues Cys146 and Glu118. The rearrangement of H-bond pattern, pi-pi interactions, and strong hydrophobic interactions were observed at both the binding sites. The allosteric pocket inhibitor exhibited improved binding energy than the normal site inhibitor based on MMGBSA and MMPBSA analysis. With subsequent characterization, the current study reveals the allosteric binding site and provides insights into the drug binding mechanism of DSPI. Communicated by Ramaswamy H. Sarma
机译:DSPI是一种推测的烯醇基辅酶a(CoA)水合酶/异构酶,预计将参与合成顺-2-癸烯酸(CDA),这是一种存在于超级细菌铜绿假单胞菌中的群体感应(QS)信号分子。目前的研究不仅为小分子调节剂的清晰设计采用了广谱策略,还为DSPI提供了新的变构抑制剂,以研究其作为治疗靶点的功能和潜力。对接分析显示,结合到特定变构位点的化合物10252273与活性结合袋的独特氨基酸残基Glu118相互作用,因此表明存在竞争性变构位点。因此,目前的研究通过靶向正常结合位点来识别和表征抑制剂,并报告了在与正常位点相同的结合通道中存在competo变构位点。分子对接研究提出了两种化合物,它们共享一个苯甲酰胺-苯并咪唑(BB)主链,作为有效的抑制剂,可以通过靶向正常和提议的变构结合位点来阻断DSPI的机制。MD模拟进一步揭示了由于关键残基Cys146和Glu118的置换,正常结合位点被破坏。在两个结合位点都观察到了氢键模式的重排、π-π相互作用和强烈的疏水相互作用。基于MMGBSA和MMPBSA分析,变构口袋抑制剂显示出比正常位点抑制剂更好的结合能。通过随后的表征,目前的研究揭示了变构结合位点,并对DSPI的药物结合机制提供了见解。由拉玛斯瓦米·H·萨尔玛传达

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