An integrated computational bioprospection of flavonoids as modulators of Mycobacterium tuberculosis decaprenylphosphoryl-β-d-ribose-2′-epimerase 1

IF 3.1 4区生物学 Q2 BIOLOGY

Computational Biology and Chemistry Pub Date : 2025-10-08 DOI:10.1016/j.compbiolchem.2025.108719

Kakudji Kisimba , Rukayat Abiola Abdulsalam , Elliasu Y. Salifu , Saheed Sabiu , Mbuso Faya

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引用次数: 0

Abstract

Tuberculosis (TB) remains a significant global health threat, claiming millions of lives annually despite being preventable. The emergence of drug-resistant strains, including extensively drug-resistant TB (XDR-TB) and multidrug-resistant TB (MDR-TB), severely limits conventional treatment options. Furthermore, commonly used TB medications like isoniazid (INH) and rifampicin (RIF) are associated with adverse side effects. Consequently, researchers increasingly explore natural products as potential sources for novel anti-TB therapeutics. This study investigated the inhibitory potential of 103 flavonoid compounds with documented antimycobacterial activity against TB. Focusing on decaprenylphosphoryl-β-D-ribose 2′-epimerase 1 (DprE1) as a druggable target, we employed molecular docking, pharmacokinetic evaluation, and 200-ns molecular dynamics simulations to assess stability and energy refinement. Our results showed that the top five compounds exhibited more favourable binding free energy values against DprE1 than the standard, PBTZ169. Notably, cycloartobiloxanthone demonstrated a binding free energy of −63.67 kcal/mol, surpassing PBTZ169 (-37.78 kcal/mol). Structural analysis revealed that cycloartobiloxanthone stabilised the protein and formed additional interactions without compromising its integrity. These findings suggest a potential structural mechanism for the inhibitory action of cycloartobiloxanthone against Mycobacterium tuberculosis DprE1. While this study highlights the potential of cycloartobiloxanthone as a lead compound, further validation through in vivo and in vitro studies is recommended.

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黄酮类化合物作为结核分枝杆菌十戊烯基磷酸化-β-d-核糖-2 ' - epimase 1调节剂的综合计算生物展望

结核病仍然是一个重大的全球健康威胁，尽管可以预防，但每年仍夺去数百万人的生命。耐药菌株的出现，包括广泛耐药结核病（XDR-TB）和耐多药结核病（MDR-TB），严重限制了常规治疗方案。此外，常用的结核病药物如异烟肼（INH）和利福平（RIF）与不良副作用有关。因此，研究人员越来越多地探索天然产物作为新型抗结核治疗的潜在来源。本研究考察了103种具有抑菌活性的类黄酮化合物对结核病的抑制潜力。以十烯丙基磷酸基-β- d -核糖2 ' -epimerase 1 （DprE1）为靶点，采用分子对接、药代动力学评价和200-ns分子动力学模拟来评估其稳定性和能量细化。结果表明，前5个化合物对DprE1的结合自由能值比标准化合物PBTZ169更有利。值得注意的是，cycloartobiloxanthone的结合自由能为- 63.67 kcal/mol，超过了PBTZ169（-37.78 kcal/mol）。结构分析表明，环artobiloxanthone稳定了蛋白质，并在不损害其完整性的情况下形成了额外的相互作用。这些发现提示了环artobiloxanthone对结核分枝杆菌DprE1抑制作用的潜在结构机制。虽然本研究强调了环artobiloxanthone作为先导化合物的潜力，但建议通过体内和体外研究进一步验证。

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来源期刊

Computational Biology and Chemistry 生物-计算机：跨学科应用

CiteScore

6.10

自引率

3.20%

发文量

142

审稿时长

24 days

期刊介绍： Computational Biology and Chemistry publishes original research papers and review articles in all areas of computational life sciences. High quality research contributions with a major computational component in the areas of nucleic acid and protein sequence research, molecular evolution, molecular genetics (functional genomics and proteomics), theory and practice of either biology-specific or chemical-biology-specific modeling, and structural biology of nucleic acids and proteins are particularly welcome. Exceptionally high quality research work in bioinformatics, systems biology, ecology, computational pharmacology, metabolism, biomedical engineering, epidemiology, and statistical genetics will also be considered. Given their inherent uncertainty, protein modeling and molecular docking studies should be thoroughly validated. In the absence of experimental results for validation, the use of molecular dynamics simulations along with detailed free energy calculations, for example, should be used as complementary techniques to support the major conclusions. Submissions of premature modeling exercises without additional biological insights will not be considered. Review articles will generally be commissioned by the editors and should not be submitted to the journal without explicit invitation. However prospective authors are welcome to send a brief (one to three pages) synopsis, which will be evaluated by the editors.