Mechanistic insights into Ginkgo biloba leaves against cisplatin-induced ototoxicity: An approach combining network...

Although Ginkgo biloba leaves (GBLs) extract exhibits considerable therapeutic potential for alleviating cisplatin-induced ototoxicity (CIO), its exact molecular mechanisms remain unclear. In this study, we investigated the potential therapeutic mechanisms of GBLs against CIO by integrating network pharmacology with molecular docking and molecular dynamics simulations.

Active components and potential targets of GBLs were identified through the TCMSP, SEA, and SuperPred databases. CIO-related disease targets were obtained using GenCLiP 3 and CTD databases. Common targets associated with both the active components and CIO were determined using the Venny tool. Through network construction and analysis, the major active components and key targets were identified. Gene enrichment analysis was performed using the DAVID platform. The binding activity between the major active components and key targets was evaluated using molecular docking. The stability of the binding conformations of the high-affinity complexes was validated using molecular dynamics simulations. Pharmacokinetic properties of the major active components were comprehensively evaluated using SwissADME.

In total, 26 active components from GBLs and 105 intersecting targets were identified. The main active components of GBLs against CIO were quercetin, luteolin, genkwanin, kaempferol, chrysoeriol, ginkgolide B, and bilobalide. The key targets included HIF1A, HSP90AA1, MTOR, NFKB1, STAT3, and TNF. Gene enrichment analysis revealed that the otoprotective effects of GBLs were primarily involved in the inflammatory response, positive regulation of apoptotic process, and response to hypoxia,‌ and were closely associated with the HIF-1, sphingolipid, IL-17, Toll-like receptor, PI3K-Akt, and NOD-like receptor signaling pathways‌. Molecular docking analysis demonstrated strong binding affinities between the main active components and key targets. Molecular dynamics simulations indicated that both the ginkgolide B-MTOR and luteolin-TNF complexes maintained stable binding conformations. Most of the main active components exhibited favorable pharmacokinetic properties.

This study highlights the therapeutic potential of GBLs in alleviating CIO and clarifies the possible molecular mechanisms involved. However, these findings remain merely predictive and require validation through in vitro and in vivo experiments.