并评估更生霉素 X 和更生霉素 D 作为有效的抗结核药物。
and evaluations of actinomycin Xand actinomycin D as potent anti-tuberculosis agents.
机构信息
Department of Pharmaceutics, Unaizah College of Pharmacy, Qassim University, Unaizah, Al-Qassim, Saudi Arabia.
Department of Pharmaceutical Chemistry and Pharmacognosy, Unaizah College of Pharmacy, Qassim University, Unaizah, Al-Qassim, Saudi Arabia.
出版信息
PeerJ. 2023 Mar 8;11:e14502. doi: 10.7717/peerj.14502. eCollection 2023.
BACKGROUND
Multidrug-resistant tuberculosis (MDR-TB) is one of the world's most devastating contagious diseases and is caused by the MDR- (MDR-Mtb) bacteria. It is therefore essential to identify novel anti-TB drug candidates and target proteins to treat MDR-TB. Here, and studies were used to investigate the anti-TB potential of two newly sourced actinomycins, actinomycin-X (act-X) and actinomycin-D (act-D), from the strain UKAQ_23 (isolated from the Jubail industrial city of Saudi Arabia).
METHODS
The anti-TB activity of the isolated actinomycins was assessed using the Mtb H37Ra, (BCG), and Mtb H37Rv bacterial strains, using the Microplate Alamar Blue Assay (MABA) method. molecular docking studies were conducted using sixteen anti-TB drug target proteins using the AutoDock Vina 1.1.2 tool. The molecular dynamics (MD) simulations for both actinomycins were then performed with the most suitable target proteins, using the GROningen MAchine For Chemical Simulations (GROMACS) simulation software (GROMACS 2020.4), with the Chemistry at HARvard Macromolecular Mechanics 36m (CHARMM36m) forcefield for proteins and the CHARMM General Force Field (CGenFF) for ligands.
RESULTS
results for the Mtb H37Ra, BCG, and Mtb H37Rv strains showed that act-X had minimum inhibitory concentration (MIC) values of 1.56 ± 0.0, 1.56 ± 0.0, and 2.64 ± 0.07 µg/mL and act-D had MIC values of 1.56 ± 0.0, 1.56 ± 0.0, and 1.80 ± 0.24 µg/mL respectively. The molecular docking results showed that protein kinase PknB was the preferred target for both actinomycins, while KasA and pantothenate synthetase were the least preferred targets for act-Xand act-D respectively. The molecular dynamics (MD) results demonstrated that act-X and act-D remained stable inside the binding region of PknB throughout the simulation period. The MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) binding energy calculations showed that act-X was more potent than act-D.
CONCLUSION
In conclusion, our results suggest that both actinomycins X and D are highly potent anti-TB drug candidates. We show that act-Xis better able to antagonistically interact with the protein kinase PknB target than act-D, and thus has more potential as a new anti-TB drug candidate.
背景
耐多药结核病（MDR-TB）是世界上最具破坏性的传染病之一，由耐多药（MDR-）细菌引起。因此，识别新型抗结核药物候选物和靶蛋白来治疗 MDR-TB 至关重要。在这里，使用 和 研究来研究两种新来源的放线菌素，放线菌素 -X（act-X）和放线菌素-D（act-D），从 UKAQ_23 菌株（从沙特阿拉伯朱拜勒工业城分离）的抗结核潜力。
方法
使用 Mtb H37Ra、BCG 和 Mtb H37Rv 细菌菌株，使用微量板阿尔玛蓝测定法（MABA）方法评估分离放线菌素的抗结核活性。使用 AutoDock Vina 1.1.2 工具对十六种抗结核药物靶蛋白进行 分子对接研究。然后，使用最适合的靶蛋白对两种放线菌素进行分子动力学（MD）模拟，使用 Groningen 用于化学模拟的机器（GROMACS）模拟软件（GROMACS 2020.4），使用蛋白质的哈佛大分子力学 36m（CHARMM36m）力场和配体的 CHARMM 通用力场（CGenFF）。
结果
Mtb H37Ra、BCG 和 Mtb H37Rv 菌株的结果表明，act-X 的最小抑菌浓度（MIC）值分别为 1.56 ± 0.0、1.56 ± 0.0 和 2.64 ± 0.07 µg/mL，而 act-D 的 MIC 值分别为 1.56 ± 0.0、1.56 ± 0.0 和 1.80 ± 0.24 µg/mL。 分子对接结果表明，蛋白激酶 PknB 是两种放线菌素的首选靶标，而 KasA 和泛酸合成酶是 act-X 和 act-D 最不喜欢的靶标。分子动力学（MD）结果表明，在整个模拟过程中，act-X 和 act-D 都稳定地存在于 PknB 的结合区域内。MM/GBSA（分子力学/广义 Born 表面积）结合能计算表明，act-X 比 act-D 更有效。
结论
总之，我们的研究结果表明，放线菌素 X 和 D 都是很有前途的抗结核药物候选物。我们表明，act-X 比 act-D 更能拮抗地与蛋白激酶 PknB 靶标相互作用，因此作为一种新的抗结核药物候选物具有更大的潜力。
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