Identification of potential non-nucleoside MraY inhibitors for tuberculosis chemotherapy using structure-based virtual screening.
Identification of potential non-nucleoside MraY inhibitors for tuberculosis chemotherapy using structure-based virtual screening.
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使用基于结构的虚拟筛选鉴定用于结核病化疗的潜在非核苷MraY抑制剂。
DOI：
10.1080/07391102.2020.1862705
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发表时间：
2022-07
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
--
作者：
结核病的病原体--结核分枝杆菌(Mtb)耐药菌株的增加，对限制结核病疫情传播的努力构成了挑战。发现作用于新的或未开发的靶点的新的化学支架对于击败这种耐药病原体至关重要。Mray(磷酸-MurNAc-五肽转位酶或转位酶I)是体内验证的抗菌药物发现的靶点。核苷类天然产物体内疗效较差，可抑制mray。目前的研究集中在发现新的化学实体，特别是非核苷小分子，作为具有抗结核活性的MraYMtb抑制剂。在没有报道MraYMtb的X射线晶体结构的情况下，我们使用了基于同源模型的虚拟筛选方法和基于配体的电子药效团筛选相结合的方法。我们使用GOLD软件从ZINC15数据库中筛选出约1200万种可用于商业用途的化合物。使用双管齐下的筛选方法筛选得到的命中结果，该方法包括电子药效团假设和使用Glide对接MraYMtb同源模型。基于Glide分数和最佳结合相互作用的进一步聚类导致了15个电子点击。我们对三个排名最好的化合物和另外一个排名较差的化合物进行了分子动力学(MD)模拟，以详细分析相互作用模式。分子动力学模拟表明，化合物与mray活性部位的关键残基之间存在稳定的相互作用，这对维持酶活性至关重要。这些在硅胶上的成功可能会推动抗菌药物的发现活动，以寻找用于结核病治疗的新的mray抑制剂。
The efforts to limit the spread of the tuberculosis epidemic have been challenged by the rise of drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. It is critical to discover new chemical scaffolds acting on novel or unexploited targets to beat this drug-resistant pathogen. MraY (phospho-MurNAc-pentapeptide translocase or translocase I) is an in vivo validated target for antibacterials-discovery. MraY is inhibited by nucleoside-based natural products that suffer from poor in vivo efficacy. The current study is focused on discovering novel chemical entities, particularly, non-nucleoside small molecules, as MraYMtb inhibitors possessing antituberculosis activity. In the absence of any reported X-ray crystal structures of MraYMtb, we used a homology model-based virtual screening approach combined with the ligand-based e-pharmacophore screening. We screened ~12 million commercially available compounds from the ZINC15 database using GOLD software. The resulting hits were filtered using a 2-pronged screening method comprising e-pharmacophore hypotheses and docking against the MraYMtb homology model using Glide. Further clustering based on Glide scores and optimal binding interactions resulted in 15 in silico hits. We performed molecular dynamics (MD) simulations for the three best-ranking compounds and one other poorer-ranking compound, out of the 15 in silico hits, to analyze the interaction modes in detail. The MD simulations indicated stable interactions between the compounds and key residues in the MraY active site that are crucial for maintaining the enzymatic activity. These in silico hits could advance the antibacterial drug discovery campaign to find new MraY inhibitors for tuberculosis treatment.
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DOI：
10.1126/science.1236501
发表时间：
2013-08-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chung BC;Zhao J;Gillespie RA;Kwon DY;Guan Z;Hong J;Zhou P;Lee SY
通讯作者：
Lee SY
影响因子：
64.8
作者：
Chung BC;Mashalidis EH;Tanino T;Kim M;Matsuda A;Hong J;Ichikawa S;Lee SY
通讯作者：
Lee SY
影响因子：
8.6
作者：
Ebejer JP;Charlton MH;Finn PW
通讯作者：
Finn PW
影响因子：
3.4
作者：
Koppermann S;Cui Z;Fischer PD;Wang X;Ludwig J;Thorson JS;Van Lanen SG;Ducho C
通讯作者：
Ducho C
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML