Predicting the Drug Safety for Traditional Chinese Medicine through a Comparative Analysis of Withdrawn Drugs Using Pharmacological Network

Abstract

As the major issue to limit the use of drugs, drug safety leads to the attrition or failure in clinical trials of drugs. Therefore, it would be more efficient to minimize therapeutic risks if it could be predicted before large-scale clinical trials. Here, we integrated a network topology analysis with cheminformatics measurements on drug information from the DrugBank database to detect the discrepancies between approved drugs and withdrawn drugs and give drug safety indications. Thus, 47 approved drugs were unfolded with higher similarity measurements to withdrawn ones by the same target and confirmed to be already withdrawn or discontinued in certain countries or regions in subsequent investigations. Accordingly, with the 2D chemical fingerprint similarity calculation as a medium, the method was applied to predict pharmacovigilance for natural products from an in-house traditional Chinese medicine (TCM) database. Among them, Silibinin was highlighted for the high similarity to the withdrawn drug Plicamycin although it was regarded as a promising drug candidate with a lower toxicity in existing reports. In summary, the network approach integrated with cheminformatics could provide drug safety indications effectively, especially for compounds with unknown targets or mechanisms like natural products. It would be helpful for drug safety surveillance in all phases of drug development.

Figure 1

The network of approved drugs to targets from DrugBank, in which approved drugs are shown with blue filled spots and targets are exhibited by magenta ones.

Figure 2

The network of withdrawn drugs to targets from DrugBank, where withdrawn drugs are represented by blue filled spots and targets are shown with magenta ones.

Figure 3

Degree distribution statistics for nodes of withdrawn drugs (a) and approved drugs (b) in corresponding drug-target networks, respectively.

Figure 4

The network of critical factors resulting in drug withdrawals to the 66 withdrawn drugs from DrugBank, in which withdrawn drugs are shown with pink filled spots while adverse-effect records for them are exhibited by filled diamonds with different colors.

Figure 5

Proportion statistics of 47 approved drugs discontinued versus still launched which are greatly similar to withdrawn ones with similarity values more than 0.7, in which discontinued ones are shown in black with launched ones in red.