Drug Repurposing Research For Dry Eye Disease

Dry eye disease(DED)is a common ocular surface disorder that severely impairs visual function,thus affecting quality of life.With the ubiquitous use of electronic devices in modern life,prolonged use of video display terminals can lead to video display terminal-related DED,while staying up late,long-term wear of contact lenses,and poor eye makeup habits can all contribute to DED.Despite many studies and trials in recent years,no better treatment options for DED have been developed.Recent research has shown that the pathophysiology of DED mainly involves the inflammatory pathway,making it a promising new avenue for drug development.Drug repurposing is a drug discovery approach that involves the utilization of existing drugs for the treatment of novel indications.Based on the fact that the new drug Lifitegrast can block the binding of LFA-1 to ICAM-1,this study aims to use drug repositioning to explore,design,and optimize candidate drugs that inhibit LFA-1/ICAM-1 interaction as targets for DED.Additionally,since DED may involve pathways beyond LFA-1/ICAM-1,drug repositioning based on the drug-disease network will also be conducted to further explore new drugs for treating DED.This study is of a publishable standard for a scientific journal.This study employed three drug repositioning methods to predict candidate drugs for treating dry eye disease by inhibiting the LFA-1/ICAM-1 interaction.First,the amino acid sequence information of the drug targets LFA-1 and ICAM-1,as well as the SMILES sequence information of 2565 approved drugs in Drug Bank,were used as inputs.Deep learning models,including Deep Purpose and Deep DTA(including KIBA and DAVIS training models),were used to predict drug-target interaction scores and screen for drug molecules with scores higher than that of lifitegrast.Finally,the intersection of the results yielded three repurposable drugs: deflazacort,ciclesonide,and spiramycin.Subsequently,based on the binding conformation of lifitegrast with the αL domain of LFA-1,the development and design principles of lifitegrast,and the crystal structure of the LFA-1/ICAM-1 complex,the binding pockets of the LFA-1/ICAM-1 interaction were used as docking sites for 2432 approved small molecule drugs using Auto Dock Vina.Virtual screening was performed in batches,and drugs with scores higher than that of lifitegrast were selected by comparing the predicted binding affinity of the drugs.As a result,81 drugs were found to bind to the αL domain of LFA-1 and 82 drugs were found to bind to ICAM-1.In addition,the Drug Rep network server was used to predict the top200 drugs with binding affinity to both LFA-1 and ICAM-1.The intersection of the top200 drugs predicted by Auto Dock Vina and Drug Rep yielded dexamethasone metasulfobenzoate as a candidate drug for treating dry eye disease.Furthermore,the intersection of the top 200 drugs predicted by five sets of methods,including Auto Dock Vina,Drug Rep,Deep Purpose,and Deep DTA,yielded six drugs,including deflazacort,ciclesonide,mecobalamin,tacrolimus,dihydroergotamine,and lifitegrast,which were predicted by all three sets of methods for both LFA-1 and ICAM-1.These results indicated that the candidate drugs predicted by these drug repositioning methods could be mutually confirmed,and that the virtual screening drugs could serve as potential candidates for inhibiting the LFA-1/ICAM-1 interaction.Finally,based on the drug-disease network model SAve RUNNER,133 candidate drugs with p-values less than 0.05 related to dry eye disease were predicted.The He TDR model was used to predict the top 10 drugs with similarity scores related to dry eye disease,including ephedrine and other drugs that contradicted the therapeutic effect of dry eye disease.Comparing the results of drug repositioning with and without known drug targets,it was found that the prediction performance was better when there were clear drug targets.Overall,this study utilized multiple drug repurposing methods to predict 8 candidate drugs(Deflazacort,Ciclesonide,Mecobalamin,Tacrolimus,Dihydroergotamine,Lifitegrast,Dexamethasone metasulfobenzoate,and Sirolimus)that inhibit the LFA-1/ICAM-1 interaction.Lifitegrast is an FDA-approved drug for the treatment of dry eye disease,while Tacrolimus is used off-label to treat the disease.Mecobalamin can be taken orally with vitamin B1 to alleviate dry eye symptoms,and Dexamethasone metasulfobenzoate can be used in combination with antibiotics,such as tobramycin and dexamethasone,to treat dry eye disease.Sirolimus in a lipid-based formulation has been studied for subconjunctival administration to treat non-responsive dry eye disease.Of these,three drugs(Deflazacort,Ciclesonide,and Dihydroergotamine)were newly identified in this study as potential treatments for dry eye disease.The results of this study are supported by relevant research evidence,and therefore have a certain feasibility.