Introduction

UDP-N-acetylmuramic-alanine ligase (MurC) is an enzyme catalyzing the addition of L-alanine to UDP-acetylmuramoyl nucleotide precursor in Mycobacterium tuberculosis (M. tuberculosis). This enzyme is a prerequisite for the biosynthesis of the peptidoglycans in M. tuberculosis.

Aim

This study aimed to identify the novel inhibitors of MurC using in silico approach.

Materials and Methods

The three dimensional (3D) structure of MurC was determined using comparative modeling and based on the template obtained from Haemophilus influenza (1P31). The structural analysis of the model structure shown that three residues (Lys126, Glu170, and Glu358) are critical for in the catalytic activity of the enzyme, and their inhibition will block the function of the enzyme. Ten thousand and ninety-five (10095) compounds obtained through virtual screening against Zinc and PubChem databases based on their ability to bind to MurC with minimum binding energies. These ligands screened for the physicochemical properties, molecular docking, and pharmacokinetic analyses.

Finding

Six compounds had desirable physicochemical and pharmacokinetic properties with excellent binding energy ranged between −12.27 and −10.09 kcal/mol. These compounds subjected to Molecular Dynamic (MD) Simulation and Molecular Mechanics Generalized Born Surface Area (MM-GBSA) analyses. The outcome of the analysis revealed that four ligands (PubChem1548994, ZINC11882115, ZINC22241774, and ZINC12330603) formed a stable conformation in the substrate-binding site of the protein during the 50 ns MD simulation.

Conclusion

Therefore, the ligands mentioned above might regard as novel inhibitors of M. tuberculosis which requires further in vitro and in vivo validation.

中文翻译：

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通过虚拟筛选和毒性分析比较结核分枝杆菌的UDP-N-乙酰基村酰基-丙氨酸连接酶（MurC）的比较建模和动态模拟。

介绍

UDP- Ñ -acetylmuramic丙氨酸连接酶（MURC）是催化加入L-丙氨酸对UDP-乙酰基核苷酸前体物质在酶结核分枝杆菌（中号。结核）。这种酶是在肽聚糖的生物合成的先决条件中号。肺结核。

目标

这项研究旨在使用计算机方法鉴定新型MurC抑制剂。

材料和方法

使用比较模型并基于从流感嗜血杆菌（1P31）获得的模板，确定MurC的三维（3D）结构。对模型结构的结构分析表明，三个残基（Lys126，Glu170和Glu358）对于酶的催化活性至关重要，并且它们的抑制作用会阻断酶的功能。通过对Zinc和PubChem数据库进行虚拟筛选，根据它们以最小的结合能与MurC结合的能力，获得了109（10095）种化合物。这些配体筛选了理化性质，分子对接和药代动力学分析。

寻找

六种化合物具有理想的物理化学和药物动力学特性，结合能在-12.27至-10.09 kcal / mol之间。对这些化合物进行了分子动力学（MD）模拟和分子力学广义生表面积（MM-GBSA）分析。分析结果表明，在50 ns MD模拟过程中，四个配体（PubChem1548994，ZINC11882115，ZINC22241774和ZINC12330603）在蛋白质的底物结合位点形成了稳定的构象。

结论

因此，上述配体可被视为M的新抑制剂。结核病，需要进一步的体外和体内验证。