Feng Yiyang, Feng Wenli, Yang Jing, Ma Yan
Department of Dermatovenereology, The Second Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.
Front Pharmacol. 2025 Jul 14;16:1578749. doi: 10.3389/fphar.2025.1578749. eCollection 2025.
BACKGROUND: Autophagy induced by itraconazole and ritonavir was found involved in the pathogenesis of . This study was designed to explore the possible molecular mechanism of itraconazole and ritonavir in the treatment of infection through autophagy pathway. METHODS: The overlapping targets of itraconazole and ritonavir, and those-related to and autophagy were screened. Then the core targets were identified by protein-protein interaction (PPI) network analysis. Gene enrichment analysis of targets and the drug-target-pathway-disease network was constructed. The interactions between itraconazole, ritonavir and core targets were analyzed by molecular docking and molecular dynamics simulation. Finally, the core target-miRNA interaction network was constructed to predict candidate miRNAs. RESULTS: PPI network showed that PIK3R1, RELA, STAT3, HSP90AA1, TP53, JUN, GRB2, EGFR, ESR1 and TNF were potential core targets of autophagy therapy for infection with itraconazole and ritonavir. Enrichment analysis showed that the two drugs may regulate the autophagy process through pathways including PI3K-AKT, IL-17, MAPK, Toll-like receptor, JAK-STAT and NF-κB. Molecular docking analysis indicated that itraconazole and ritonavir possess strong binding affinities with the cote target proteins, with binding free energies ranging from -5.6 to -9.5 kcal/mol. Key interactions were identified at the active sites of the targets, suggesting stable ligand-receptor complex formation. Itraconazole docked to PIK3R1 through SER-78 and GLU-82 (-9.3 kcal/mol), and ritonavir docked to PIK3R1 through ASN-85, GLU-1011 and arginine (ARG)-1088 (-7.7 kcal/mol). Molecular dynamics simulation of itraconazole and ritonavir with representative target genes lasted for 100 ns showed the structures of the formed complexes remained stable throughout. Finally, the candidate miRNAs including miR-486-5p, miR-411-5p.1 and miR-296-5p were identified. CONCLUSION: Network pharmacological analysis showed a multi-target and multi-pathway molecular mechanism of itraconazole and ritonavir in the treatment of infection, and provided a theoretical basis for subsequent studies.
背景：发现伊曲康唑和利托那韦诱导的自噬参与了……的发病机制。本研究旨在探讨伊曲康唑和利托那韦通过自噬途径治疗……感染的可能分子机制。 方法：筛选伊曲康唑和利托那韦的重叠靶点以及与……和自噬相关的靶点。然后通过蛋白质-蛋白质相互作用（PPI）网络分析确定核心靶点。对靶点进行基因富集分析并构建药物-靶点-途径-疾病网络。通过分子对接和分子动力学模拟分析伊曲康唑、利托那韦与核心靶点之间的相互作用。最后，构建核心靶点-微小RNA相互作用网络以预测候选微小RNA。 结果：PPI网络显示，PIK3R1、RELA、STAT3、HSP90AA1、TP53、JUN、GRB2、EGFR、ESR1和TNF是伊曲康唑和利托那韦治疗……感染的自噬疗法潜在核心靶点。富集分析表明，这两种药物可能通过PI3K-AKT、IL-17、MAPK、Toll样受体、JAK-STAT和NF-κB等途径调节自噬过程。分子对接分析表明，伊曲康唑和利托那韦与核心靶点蛋白具有很强的结合亲和力，结合自由能范围为-5.6至-9.5千卡/摩尔。在靶点的活性位点鉴定出关键相互作用，表明形成了稳定的配体-受体复合物。伊曲康唑通过SER-78和GLU-82与PIK3R1对接（-9.3千卡/摩尔），利托那韦通过ASN-85、GLU-1011和精氨酸（ARG）-1088与PIK3R1对接（-7.7千卡/摩尔）。伊曲康唑和利托那韦与代表性靶基因的分子动力学模拟持续100纳秒，结果表明形成的复合物结构在整个过程中保持稳定。最后，鉴定出候选微小RNA，包括miR-486-5p、miR-411-5p.1和miR-296-5p。 结论：网络药理学分析显示了伊曲康唑和利托那韦治疗……感染的多靶点、多途径分子机制，为后续研究提供了理论依据。
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