破译 5FDQD 的作用机制和为 FMN 核糖开关设计新的中性类似物：一个温和的元动力学模拟研究,Physical Chemistry Chemical Physics

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破译 5FDQD 的作用机制和为 FMN 核糖开关设计新的中性类似物：一个温和的元动力学模拟研究
Physical Chemistry Chemical Physics ( IF 2.9 ) Pub Date : 2021-11-29 , DOI: 10.1039/d1cp01348c
Padmaja D Wakchaure _{1,

2} , Bishwajit Ganguly _{1,

2}

Affiliation

FMN 核糖开关是用于设计新抗生素的新药物靶点，并且已经努力设计新的带电和不带电的配体。不带电荷的配体显示出不需要任何转运蛋白进行细胞内转运或不需要蛋白质进行磷酸化的优势。5FDQD（5-（3-（4-氟苯基）丁基）-7,8-二甲基吡啶并（3,4- b）喹喔啉-1,3（2 H ,5 H）-二酮）是最近报道的一种中性配体FMN 核糖开关对艰难梭菌有活性小鼠感染。然而，5FDQD结合的FMN核糖开关的晶体结构尚不清楚，配体结合和触发核糖开关功能的机制尚不清楚。我们使用温和的元动力学 (WT-MtD) 模拟技术检查了 5FDQD 与 FMN 核糖开关的结合亲和力。FMN核糖开关的晶体结构表明，FMN通过磷酸基团与G62相互作用；然而，不带电荷的配体利用 π-π 堆积相互作用与从 WT-MtD 模拟结果观察到的相同的核糖开关残基。模拟结果表明，5FDQD 中苯环上氟的存在对于增强中性配体与 FMN 核糖开关的结合亲和力很重要。WT-MtD 结果表明，1、与 5FDQD 相比，5FDQD 中苯环上的 2-二氟取代（FMN-difluoro2）和苯环中的 1,3 位（FMN-difluoro1）与 FMN 核糖开关的结合能较弱。在苯环的 5 位取代另一个氟原子（FMN-三氟）显示出相当的结合亲和力（~-31.4 kcal mol⁻¹ ) 到 5FDQD。与 5FDQD 相比，苯环上的给电子取代（例如氨基）也降低了与核糖开关的结合亲和力（-28.8 kcal mol^-1）。计算结果表明，不带电配体苯环中取代的位置和性质影响整体结合，这种微妙的平衡对于实现与 FMN 核糖开关的优异结合亲和力很重要。

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Deciphering the mechanism of action of 5FDQD and the design of new neutral analogues for the FMN riboswitch: a well-tempered metadynamics simulation study

The FMN riboswitch is a novel drug target for the design of new antibiotics, and efforts have been made to design new charged and uncharged ligands. Uncharged ligands have shown advantages of not requiring any transporter for intracellular transport or proteins for their phosphorylation. 5FDQD (5-(3-(4-fluorophenyl)butyl)-7,8-dimethylpyrido(3,4-b)quinoxaline-1,3(2H,5H)-dione) is a recently reported neutral ligand for the FMN riboswitch active against Clostridium difficile infection in mice. However, the crystal structure of the 5FDQD bound FMN riboswitch is not available, and the mechanism of ligand binding and triggering the function of the riboswitch is not well understood. We have examined 5FDQD for its binding affinity with the FMN riboswitch using the well-tempered metadynamics (WT-MtD) simulation technique. The crystal structure of the FMN riboswitch shows that the FMN interacts with the J4/5 region through the phosphate group with G62; however, the uncharged ligands take advantage of π–π stacking interactions with the same residue of the riboswitch observed from the WT-MtD simulation results. The simulation results show that the presence of fluorine on the phenyl ring in 5FDQD is important to enhance the binding affinity of the neutral ligands with the FMN riboswitch. The WT-MtD results showed that the 1,2-difluoro substitution on the phenyl ring in 5FDQD (FMN-difluoro2) and the 1,3 positions in the phenyl ring (FMN-difluoro1) showed weaker binding energy with the FMN riboswitch compared to 5FDQD. The substitution of another fluorine atom at the 5-position of the phenyl ring (FMN-trifluoro) showed a comparable binding affinity (∼−31.4 kcal mol⁻¹) to 5FDQD. Electron-donating substitution on the phenyl ring such as the amino group also lowered the binding affinity (−28.8 kcal mol⁻¹) with the riboswitch compared to 5FDQD. The computed results suggest that the position and nature of substitution in the phenyl ring of the uncharged ligands affect the overall binding and such a delicate balance is important to achieve superior binding affinity with the FMN riboswitch.

更新日期：2021-12-20

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