Discovery Of Drug Repositioning On Adverse Drug Reactions

Drug repositioning(also called drug repurposing,reprofiling),a strategy for exploring outside the scope of the existing medical indication new uses for approved drugs or clinical candidates,has multiple advantages over de novo drug development:it can reduce the period for drug development,it needs less investment with lower risk of failure,it may reveal new pathways and targets.And it also provides foundation of the mechanism of drug action and toxicology.Accordingly,repositioning of‘old’drugs to treat diseases is progressively becoming a glamorous proposal in the field of drug research and development(R&D).Up to now,many methods for computer-aided drug repurposing have been developed.However,a few types of research have carried out on the similarity of drugdrug pairs.We collected the ADR(Adverse Drug Reaction)and ATC(Anatomical Therapeutic Chemical)code of drugs from the Adverse Drug Reaction Classification System(ADReCS)v2.2,which includes 2,151 drugs with ATC code and their corresponding 5,160 ADR Preferred Terms(PTs).Also,we obtained the information of gene expression profile under drug perturbation from The Library of Integrated Network-Based Cellular Signatures(LINCS).Using the characteristic direction(CD)method,gene profile will be regularized.We quantitated the similarity of drug-drug pairs through Tanimoto coefficient in ADR level,clinical similarity in indication level,and Euclidean distance in gene expression profile under drug perturbation.Then,drug relationship pairs were divided into three significantly different groups according to ATC 1st main group.And those with some similar indications were further analyzed.Upon above data,we carried out statistical analysis for drug repurposing from two aspects of similarity of drug pairs:ADR and gene expression profile under drug perturbation.Three hypotheses were proposed:(1)the more similar of the ADR,the more similar of the indication;(2)if drug A has the similar genetic profile with several drugs with ATC 1,the drug may also have the ATC 1;(3)if drug A has the similar ADR with several drugs with ATC 1,the drug may also have the same ATC 1.Based on our data,these three hypotheses have been proved to some extent.According to the data of ADR Tanimoto,10 possible cases of drug repurposing were found,and 50%of them have entered the phase Ⅳ.Besides,we built a drug-drug adjacency network according to the classification of indications,from which 49 highly connected modules were extracted.Drugs with fewer indications may infer new uses.Finally,in order to analyze the mechanism of drug action,we took the prediction of drug repositioning of aceclofenac as an example.From the starting point of drug development,the perturbation of genes,to follow-up of drug research,the occurrence of ADR.In summary,ADR and gene expression profile are related to the efficacy of drugs.Based on the analysis of these,the mechanism of drug action may be further understood,and guidance may be provided for drug repositioning.