Department of Pharmacology, KLE College of Pharmacy Belagavi, KLE Academy of Higher Education and Research (KAHER), Belagavi, 590010, India.
Silicon Script Sciences Private Limited, Bharatpur, Ghorahi, Dang, Nepal.
Sci Rep. 2024 Aug 5;14(1):18067. doi: 10.1038/s41598-024-66437-8.
Globoid cell leukodystrophy is a severe rare disorder characterized by white matter degradation, resulting in a progressive loss of physical and mental abilities and has extremely limited therapeutic interventions. Therefore, this study aimed to delve into the Globoid cell leukodystrophy associated intricate network of differentially expressed genes (p < 0.05, |Fc|> 1) to identify potential druggable targets and possible therapeutic interventions using small molecules. The disease-associated neuronal protein circuit was constructed and analyzed, identifying 53 nodes (minimum edge cutoff 1), among which five (FOS, FOSB, GDNF, GFRA1, and JUN) were discerned as potential core protein nodes. Although our research enumerates the potential small molecules to target various protein nodes in the proposed disease network, we particularly underscore T-5224 to inhibit c-Jun activity as JUN was identified as one of the pivotal elements within the disease-associated neuronal protein circuit. The evaluation of T-5224 binding energy (- 11.0 kcal/mol) from docking study revealed that the compound to exhibit a notable affinity towards Jun/CRE complex. Moreover, the structural integrity of complex was affirmed through comprehensive molecular dynamics simulations, indicating a stable hydrophilic interaction between T-5224 and the Jun/CRE complex, thereby enhancing protein compactness and reducing solvent accessibility. This binding energy was further substantiated by free binding analysis, revealing a substantial thermodynamics complex state (- 448.00 ± 41.73 kJ/mol). Given that this investigation is confined to a computational framework, we additionally propose a hypothetical framework to ascertain the feasibility of inhibiting the Jun/CRE complex with T-5224 against Globoid cell leukodystrophy, employing a combination of in vitro and in vivo methodologies as a prospective avenue of this study.
球样细胞脑白质营养不良是一种严重的罕见疾病，其特征是白质退化，导致身体和智力能力逐渐丧失，且治疗干预措施极其有限。因此，本研究旨在深入研究球样细胞脑白质营养不良相关的差异表达基因复杂网络（p<0.05，|Fc|>1），以确定潜在的可用药靶标和可能的治疗干预小分子。构建和分析了与疾病相关的神经元蛋白网络，确定了 53 个节点（最小边缘截止值为 1），其中 5 个（FOS、FOSB、GDNF、GFRA1 和 JUN）被认为是潜在的核心蛋白节点。尽管我们的研究列举了针对所提出的疾病网络中各种蛋白节点的潜在小分子，但我们特别强调 T-5224 抑制 c-Jun 活性，因为 JUN 被确定为疾病相关神经元蛋白网络中的关键元素之一。通过对接研究评估 T-5224 的结合能（-11.0 kcal/mol）表明，该化合物对 Jun/CRE 复合物表现出显著的亲和力。此外，通过全面的分子动力学模拟证实了复合物的结构完整性，表明 T-5224 与 Jun/CRE 复合物之间存在稳定的亲水性相互作用，从而增强了蛋白质的紧凑性并降低了溶剂的可及性。自由结合分析进一步证实了这种结合能，表明复合物的热力学状态显著（-448.00±41.73 kJ/mol）。鉴于本研究仅限于计算框架，我们还提出了一个假设框架，以确定使用 T-5224 抑制 Jun/CRE 复合物治疗球样细胞脑白质营养不良的可行性，结合体外和体内方法作为本研究的一个潜在途径。
