Network pharmacology and molecular dynamics simulations reveal shared mechanisms and myopia-specific targets of atropine in myopia and dry eye disease.

backgroundAtropine is an effective agent for myopia control; however, clinical reports have indicated potential side effects associated with inducing or exacerbating dry eye disease (DED). It remains unclear whether the therapeutic targets involved in atropine-mediated myopia control overlap with those potentially associated with ocular surface effects. Therefore, this study aimed to characterise the shared or distinct target landscape and plausible molecular pathways through which atropine may contribute to myopia control while also being associated with dry eye-related symptoms.

methodsIn silico analysis was performed to explore the molecular interactions of atropine in controlling myopia and DED. The target lists for atropine, myopia, and DED were sourced from six public databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses identified common and unique pathways. A protein-protein interaction (PPI) network was created and analysed using Cytoscape to identify hub genes using six ranking algorithms. Targets were stratified into shared Class I and myopia-prioritised Class II categories by integrating retinal and pan-ocular expression data. Molecular docking and molecular dynamics (MD) simulations were conducted to assess the binding affinities of atropine to prioritised targets.

resultsA total of 57 shared Class I and 19 Class II myopia-prioritised targets were identified; 19 hub genes were consistently ranked across the six algorithms. Class I targets converge on inflammatory and extracellular-matrix-remodelling pathways. Evidence of ocular expression supports the biological relevance of the prioritised targets in both classes. Docking showed favourable atropine binding to representative Class I targets (EGFR, MMP2, MMP9, and MAPK1) and Class II candidates (PIK3R1 and AKR1B1). MD simulations supported stable complexes for eight atropine-target pairs, with MM-PBSA binding free energy estimates supporting the computational prioritisation.

conclusionsShared Class I targets may potentially link the effects of atropine on both myopia control and DED, along with Class II targets specific to myopia, thereby generating testable hypotheses regarding the dual ocular effects of atropine and informing future mechanistic and translational studies.