Evaluating the binding potency of the carbapenem (T208) ligand and modelled non-halogen (NH2 and SH) and halogen (Br, Cl, F) derivatives in Mycobacterium tuberculosis L. D-transpeptidase

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling Pub Date : 2025-05-17 DOI:10.1016/j.jmgm.2025.109082

Duraisamy Thirumeignanam , Palanisamy Deepa , Balasubramanian Sundarakannan

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引用次数: 0

Abstract

Improvements in medication are required because number of tuberculosis (TB)-related deaths increase during COVID-19 pandemic. Reducing efficiency of current therapeutic agents require creation of novel medications that aim specific targets and avoid existing resistance mechanisms. In this study, we had focused on tuberculosis, most deadly infection, which threatens humanity in the 20th century after COVID-19, and world's leading cause of infection-related mortality. Our main goal in this study was to understand the stability and potency of carbapenem (T208) ligands and their modelled derivatives (Br, Cl, F, NH₂, and SH) through hydrogen and halogen bond interactions that holds ligand-amino acid contact in the hinge region. This information will provide a clear picture of structural and binding characteristics of protein-ligand interactions. Further, this will aid chemists in creating new carbapenem ligands, which are expected to reduce the action of β-lactamase enzyme and serve as anti-TB drugs. The binding strength of carbapenem ligands with interacting hinge region amino acid side chains: tryptophan (Trp-340), histidine (His-336), histidine (His-352), cystine (Cys 354), and tyrosine (Tyr 318) were analyzed through interaction energies calculated at HF, M062X, M06HF, B3PW91, and MP2 level of theories for various basis sets (6-311G∗∗, SDD). Overall, derivatives of halogen atoms (Br, Cl, and F) and NH₂ enhanced the binding strength of T208 in β-lactamase enzymes. This opened up a new and unique pathway for derivatives preference on ligand that perfectly encloses amino acid in the hinge region.

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评估碳青霉烯（T208）配体与模拟非卤素（NH2和SH）和卤素（Br, Cl， F）衍生物在结核分枝杆菌L. d转肽酶中的结合效力

由于COVID-19大流行期间与结核病相关的死亡人数增加，因此需要改进药物治疗。降低现有治疗药物的效率需要创造针对特定靶点并避免现有耐药机制的新药物。在这项研究中，我们将重点放在结核病上，这是继COVID-19之后在20世纪威胁人类的最致命的感染，也是世界上与感染相关的死亡的主要原因。本研究的主要目的是了解碳青霉烯（T208）配体及其模拟衍生物（Br、Cl、F、NH2和SH）的稳定性和效力，通过在铰链区保持配体和氨基酸接触的氢和卤素键相互作用。这一信息将为蛋白质-配体相互作用的结构和结合特征提供清晰的图像。此外，这将帮助化学家创造新的碳青霉烯配体，这种配体有望减少β-内酰胺酶的作用，并作为抗结核病药物。通过计算不同基组（6-311G∗∗，SDD）理论在HF、M062X、M06HF、B3PW91和MP2水平上的相互作用能，分析了碳青青烯类配体与铰链区氨基酸侧链相互作用的色氨酸（Trp-340）、组氨酸（His-336）、组氨酸（His-352）、胱氨酸（Cys 354）和酪氨酸（Tyr 318）的结合强度。总体而言，卤素原子衍生物（Br、Cl和F）和NH2增强了T208在β-内酰胺酶中的结合强度。这为衍生物在铰链区完美包裹氨基酸的配体上的优先选择开辟了一条新的独特途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of molecular graphics & modelling 生物-计算机：跨学科应用

CiteScore

5.50

自引率

6.90%

发文量

216

审稿时长

35 days

期刊介绍： The Journal of Molecular Graphics and Modelling is devoted to the publication of papers on the uses of computers in theoretical investigations of molecular structure, function, interaction, and design. The scope of the journal includes all aspects of molecular modeling and computational chemistry, including, for instance, the study of molecular shape and properties, molecular simulations, protein and polymer engineering, drug design, materials design, structure-activity and structure-property relationships, database mining, and compound library design. As a primary research journal, JMGM seeks to bring new knowledge to the attention of our readers. As such, submissions to the journal need to not only report results, but must draw conclusions and explore implications of the work presented. Authors are strongly encouraged to bear this in mind when preparing manuscripts. Routine applications of standard modelling approaches, providing only very limited new scientific insight, will not meet our criteria for publication. Reproducibility of reported calculations is an important issue. Wherever possible, we urge authors to enhance their papers with Supplementary Data, for example, in QSAR studies machine-readable versions of molecular datasets or in the development of new force-field parameters versions of the topology and force field parameter files. Routine applications of existing methods that do not lead to genuinely new insight will not be considered.