Vummidi Varalakshmi, Talluri Sekhar
Department of Biotechnology, GITAM School of Technology, GITAM, Gandhi Nagar, Rushikonda, 530045, Visakhapatnam, Andhra Pradesh, India.
Infect Disord Drug Targets. 2025;25(3):e18715265341228. doi: 10.2174/0118715265341228240827062721.
Tuberculosis is an infectious disease caused by . The current treatment protocols for pulmonary tuberculosis are quite effective, even though the treatment requires 3-6 months. The current treatment protocols for extrapulmonary tuberculosis are based on the same drugs that are used for pulmonary tuberculosis. However, the success rates are much lower for certain types of extrapulmonary tuberculosis, such as tuberculous meningitis. Tuberculous meningitis is one of the very few diseases attributable to bacteria that have a very high short-term mortality rate among diagnosed patients, even after treatment with antibiotics that are effective for pulmonary tuberculosis. For example, rifampicin is highly effective for the treatment of pulmonary tuberculosis, but its effectiveness for the treatment of tuberculous meningitis is much lower. The reason for the lower effectiveness of rifampicin against tuberculous meningitis is that it has low Blood-Brain Barrier (BBB) permeability, which results in lower concentrations of the drug at the required sites in the central nervous system.
In this work, ligands having improved BBB permeability and pharmacokinetic and pharmacodynamic properties, either similar to or better than that of rifampicin, have been designed. The BBB permeability of the designed molecules was assessed by using pkCSM, a machine- learning model. Pharmacokinetic properties, drug-likeness, and synthesizability were assessed by using SWISS-MODEL. The binding affinity of the designed drugs was assessed by using AutoDock Vina. A customized scoring function, StWN score, was used for a quantitative weighted assessment of all the properties of interest to rank the designed molecules.
In this study, drug-like ligands have been designed that have been predicted to have high BBB permeability as well as high affinity for RNA polymerase β of .
The best ligands generated by the tools employed were selected as potential drugs to address the current need for better options for the treatment of tuberculous meningitis.
结核病是由……引起的一种传染病。目前肺结核的治疗方案相当有效，尽管治疗需要3至6个月。目前肺外结核的治疗方案基于与肺结核相同的药物。然而，某些类型的肺外结核，如结核性脑膜炎，成功率要低得多。结核性脑膜炎是极少数由细菌引起的疾病之一，即使在使用对肺结核有效的抗生素治疗后，确诊患者的短期死亡率也非常高。例如，利福平对肺结核的治疗非常有效，但对结核性脑膜炎的治疗效果要低得多。利福平对结核性脑膜炎疗效较低的原因是其血脑屏障（BBB）通透性低，导致中枢神经系统所需部位的药物浓度较低。
在这项工作中，设计了具有改善的血脑屏障通透性以及与利福平相似或更好的药代动力学和药效学特性的配体。通过使用机器学习模型pkCSM评估设计分子的血脑屏障通透性。通过使用SWISS-MODEL评估药代动力学特性、药物相似性和可合成性。通过使用AutoDock Vina评估设计药物的结合亲和力。使用定制的评分函数StWN分数对所有感兴趣的特性进行定量加权评估，以对设计分子进行排名。
在本研究中，设计了类似药物的配体，预计这些配体具有高血脑屏障通透性以及对……的RNA聚合酶β 的高亲和力。
所采用工具生成的最佳配体被选为潜在药物，以满足当前对更好的结核性脑膜炎治疗选择的需求。
