汤普森环：通过靶向去甲基甲萘醌甲基转移酶蛋白的弱点进行抗结核药物设计的机会,RSC Advances

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汤普森环：通过靶向去甲基甲萘醌甲基转移酶蛋白的弱点进行抗结核药物设计的机会
RSC Advances ( IF 3.9 ) Pub Date : 2020-6-19 , DOI: 10.1039/d0ra03206a
Adeniyi T Adewumi ₁ , Opeyemi S Soremekun ₁ , Mary B Ajadi ₂ , Mahmoud E S Soliman ₁

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耐药结核病 (TB) 仍然是全球最大的健康挑战，每年估计有 1000 万人感染和 150 万人死亡。去甲基甲基萘醌甲基转移酶 ( menG ) 催化去甲基甲基萘醌转化为与结核病发病机制有关的甲基萘醌 (MK)，因此，它已成为主要的药物靶点。DG70 是一种联苯酰胺化合物，已知是menG的高结合亲和力抑制剂。本研究使用基于原子的动态模拟研究了 DG70 与menG结合后的结构和动态影响。我们的研究结果表明，menG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、一个称为 Thompson 环的 omega 样环（残基 210-220）、九个 α-螺旋、五个 β-链等。此外，基于原子的动态模拟显示Thompson 环对 DG70 的治疗活性至关重要。该环在未配体-menG结构中呈现开放构象。然而，在 DG70- menG中，它呈现出紧密闭合的构象。这解释了在能量计算中观察到的高结合亲和力（-32.48 kcal mol ^{-1 ）。}有趣的是，这些发现与menG中的构象扰动进一步协作蛋白质。总之，这项研究的见解突出了menG蛋白中的结构“阿喀琉斯之踵”，可以通过专门针对它们的抑制剂进一步利用。

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Thompson loop: opportunities for antitubercular drug design by targeting the weak spot in demethylmenaquinone methyltransferase protein

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.

更新日期：2020-06-19

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