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首页> 外文期刊>RSC Advances >Thompson loop: opportunities for antitubercular drug design by targeting the weak spot in demethylmenaquinone methyltransferase protein
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Thompson loop: opportunities for antitubercular drug design by targeting the weak spot in demethylmenaquinone methyltransferase protein

机译：Thompson Loop：通过靶向DemethylmenaOne甲基转移酶蛋白质中的弱点来实现抗细胞药物设计的机会

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Drug-resistant Tuberculosis (TB) has remained the top global health challenge, with a yearly estimation of 10 million infections and 1.5 million deaths in humans. Demethylmenaquinone methyltransferase ( menG ) catalyzes demethylmenaquinone conversion to menaquinone (MK) that is implicated in the TB pathogenesis, hence, it has become a major drug target. DG70 is a biphenyl amide compound known to be a high binding affinity inhibitor of menG . This study investigated the structural and dynamic impacts of DG70 upon binding to menG using atom-based dynamic simulation. Our findings revealed that the modeled structure of menG possesses some Rossman-like methyltransferase characteristic features including two GXG motifs, an omega-like loop (residues 210–220) called the Thompson loop, nine α-helices, five β-strands, etc. Furthermore, atom-based dynamic simulations revealed that the Thompson loop is critical in the therapeutic activity of DG70. The loop assumed an open conformation in the unliganded- menG structure. However, in the DG70- menG , it assumed a tightly closed conformation. This explains the high binding affinity (?32.48 kcal mol ~(?1) ) observed in the energy calculations. Interestingly, these findings are further collaborated by the conformational perturbation in the menG protein. Conclusively, insights from this study, highlight the structural “Achilles heel” in menG protein which can be further leveraged by inhibitors tailored to specifically target them.
机译：耐药结核病（TB）仍然是全球性健康挑战，每年估计人类1000万感染和150万人死亡。去甲基丙烯醌甲基转移酶（萌）催化去甲基辐射醌转化为苯醌（MK），其涉及Tb发病机制，因此已成为主要药物靶标。 DG70是已知为萌的高结合亲和抑制剂的联苯酰胺化合物。本研究研究了DG70在使用基于原子的动态模拟结合Meng时的结构和动态影响。我们的研究结果表明，孟的模型结构具有一些罗斯曼样甲基转移酶特征，包括两个GXG基序，欧米茄环（残基210-220）称为汤普森环，九个α-螺旋，五β股等。此外，基于原子的动态模拟显示汤普森环路在DG70的治疗活性中至关重要。该环路在销钉结构中揭开了开放构象。然而，在DG70-萌，它假设紧密闭合的构象。这解释了在能量计算中观察到的高结合亲和力（α32.48kcalmol〜（α1））。有趣的是，这些发现是通过孟蛋白的构象扰动进一步合作。最后，本研究的见解，突出了孟蛋白的结构“Achilles脚后跟”，该结构是可以通过量身定制的抑制剂进一步利用，以专门针对它们。

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