Drugs inducing interstitial lung disease: in silico analysis of their structures and targets

The molecular mechanisms underlying many drug-induced diseases, namely, the adverse effects caused by medications, remain poorly understood. As we consider that adverse effects result from the unintended targets of a drug, we aimed to clarify the molecular mechanisms of drug-induced diseases based on information regarding off-target interactions.

First, off-targets were searched in public databases, and four proteins were selected. Subsequently, rare and intractable diseases caused by drugs targeting the proteins were identified through side-effect information. Further, the pharmacological actions of the drugs on the targets and related substructures were investigated using statistical analysis and substructure search.

Of the four proteins, one of the ATP-binding cassette (ABC) transporters, ABCG2, was related to a severe disease, interstitial lung disease (ILD): drugs inducing ILD showed a strong tendency to bind and inhibit ABCG2 and kinases. Moreover, these drugs tended to contain pyrimidine and methoxyethane, both of which are effective at inhibiting ABCG2 and kinases, as substructures. Drugs satisfying both conditions of "binding to ABCG2/kinase" and "having substructure pyrimidine/methoxyethane" were more associated with ILD compared with drugs satisfying only one condition. Among the drugs reported to be associated with a high incidence of ILD, many were strong inhibitors of ABCG2 with or without kinase inhibitory activity; however, some drugs showed little evidence of binding to ABCG2 or kinases. Examples of the latter included folic acid (FA) antagonists, which are known to induce pulmonary fibrosis.

These results suggest that for kinase inhibitors known to induce ILD, inhibition of off-target ABCG2 as well as kinases is likely to be associated with the disease and that many drugs inducing ILD other than known kinase inhibitors also inhibit ABCG2. Some drugs with little evidence of binding to ABCG2 include antifolates, raising the possibility that abnormal FA metabolism is one of the common phenomena of drug-induced ILD, particularly as ABCG2 is a folate efflux transporter related to tissue folate absorption.