通过抑制聚酮合成酶13硫酯酶抑制结核分枝杆菌脂质生物合成：来自计算分析的见解

IF 4.7 3区医学 Q1 INFECTIOUS DISEASES

Journal of Infection and Public Health Pub Date : 2025-05-26 DOI:10.1016/j.jiph.2025.102835

Maha M. Alawi , Hattan S. Gattan , Azzah S. Alharbi , Mohammed H. Alruhaili , Ibrahim A. Al-Zahrani , Saad B.AL Masaud , Vivek Dhar Dwivedi , Esam I. Azhar

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引用次数: 0

摘要

由结核分枝杆菌（Mtb）引起的结核病（TB）仍然是一项全球卫生挑战，特别是随着多药耐药和广泛耐药菌株的出现。霉菌酸的生物合成对结核分枝杆菌细胞壁的完整性至关重要，提供了有希望的治疗干预靶点。聚酮合成酶13的硫酯酶结构域Pks13-TE是该途径的核心，因此是一个有吸引力的药物靶点。方法通过计算筛选1228个天然化合物文库，筛选出最具潜在活性的Pks13-TE抑制剂。基于结合亲和力，使用MTiOpenScreen对顶级候选物进行了计算机虚拟筛选。通过分子动力学模拟分析对接后验证结果的稳定性、紧凑性和灵活性等结构特性。采用MMGBSA法计算无结合能。利用FEL进一步进行构象景观分析。结果共鉴定出3个具有良好前景的化合物：ZINC000008214766、ZINC000006845076和ZINC000253498755。化合物ZINC000008214766与Pks13-TE活性位点残基形成多个氢键和范德华接触，表现出最有利的结合相互作用。MD模拟表明，它具有最小波动和紧凑构象的一致性稳定。MM/GBSA分析证实了其与其他候选药物相比具有更好的结合能力。FEL分析显示，ZINC000008214766的最小值窄而深，表明其构象稳定性强。ZINC000006845076和ZINC000253498755的结合性能中等，但稳定性较低。结论ZINC000008214766可能是抑制Pks13-TE的潜在先导化合物，为结核病的治疗提供了新的策略。这些结果还强调了在药物发现中使用计算工作流，并使人们相信天然化合物可以赢得与耐药结核病的战斗。进一步的体外和体内研究有必要验证这些发现。

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Suppressing lipid biosynthesis in Mycobacterium tuberculosis through polyketide synthase 13 thioesterase inhibition: Insights from computational analysis

Background

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health challenge, particularly with the emergence of multidrug-resistant and extensively drug-resistant strains. Mycolic acid biosynthesis is essential for the integrity of Mtb's cell wall, offering promising therapeutic intervention targets. The thioesterase domain of polyketide synthase 13, Pks13-TE, is at the heart of this pathway and, therefore, an attractive drug target.

Methods

1228 natural compound libraries were computationally screened to identify the most potentially active Pks13-TE inhibitors. In silico virtual screening was done on top candidates using MTiOpenScreen based on binding affinity. The molecular dynamics simulation was applied to analyze the structural properties in terms of stability, compactness, and flexibility of the post-validation of the docking result. The MMGBSA method was used to calculate the binding-free energy. Further conformational landscape analysis was applied using FEL.

Results

Three such promising compounds were identified: ZINC000008214766, ZINC000006845076, and ZINC000253498755. The compound ZINC000008214766 showed the most favorable binding interactions by making multiple hydrogen bonds and van der Waals contacts with Pks13-TE active site residues. MD simulations have revealed that it is consistently stable with minimal fluctuations and compact conformation. The MM/GBSA analysis confirmed its superior binding energetics compared to other candidates. The FEL analysis highlighted narrow and deep minima for ZINC000008214766, indicating strong conformational stability. Properties of ZINC000006845076 and ZINC000253498755 followed moderate binding but low stability.

Conclusions

The study underlines the possibility of ZINC000008214766 acting as a potential lead compound in inhibiting Pks13-TE and presents a new therapeutic strategy against TB. These results also highlight the use of a computational workflow in drug discovery and give cause for belief that natural compounds can win the battle against resistant TB. Further in vitro and in vivo studies are warranted to validate these findings.

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来源期刊

Journal of Infection and Public Health PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH -INFECTIOUS DISEASES

CiteScore

13.10

自引率

1.50%

发文量

203

审稿时长

96 days

期刊介绍： The Journal of Infection and Public Health, first official journal of the Saudi Arabian Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences and the Saudi Association for Public Health, aims to be the foremost scientific, peer-reviewed journal encompassing infection prevention and control, microbiology, infectious diseases, public health and the application of healthcare epidemiology to the evaluation of health outcomes. The point of view of the journal is that infection and public health are closely intertwined and that advances in one area will have positive consequences on the other. The journal will be useful to all health professionals who are partners in the management of patients with communicable diseases, keeping them up to date. The journal is proud to have an international and diverse editorial board that will assist and facilitate the publication of articles that reflect a global view on infection control and public health, as well as emphasizing our focus on supporting the needs of public health practitioners. It is our aim to improve healthcare by reducing risk of infection and related adverse outcomes by critical review, selection, and dissemination of new and relevant information in the field of infection control, public health and infectious diseases in all healthcare settings and the community.