Title : Mechanistic Insights into Side Effects of Troglitazone and Rosiglitazone Using a Novel Inverse Molecular Docking Approach
Thiazolidinediones form drugs that treat insulin resistance in type 2 diabetes mellitus. Troglitazone represents the first drug from this family, which was removed from use by the FDA due to its hepatotoxicity. As an alternative, rosiglitazone was developed, but it was under the careful FDA watch for a long time. It was suspected that it causes cardiovascular diseases, such as heart failure and stroke. We applied a novel inverse molecular docking approach to discern potential protein targets of both drugs. Troglitazone and rosiglitazone were docked into predicted binding sites of >38.000 protein structures from the Protein Data Bank and examined. Several new potential protein targets with successfully docked troglitazone and rosiglitazone were identified. The focus was devoted to human proteins so that existing or new potential side effects could be explained or proposed. Specific targets of troglitazone like 3-oxo-5-beta-steroid 4-dehydrogenase, neutrophil collagenase, stromelysin-1, and VLCAD were pinpointed, which could explain its hepatoxicity, with additional ones indicating that its application could lead to treatment/development of cancer. Results for rosiglitazone discerned its interaction with members of the matrix metalloproteinase family, which could lead to cancer and neurodegenerative disorders. The concerning cardiovascular side effects of rosiglitazone could also be explained. We firmly believe that our results deepen the mechanistic understanding of the side effects of both drugs, and potentially with further development and research, maybe even help to minimize them. The novel inverse molecular docking approach, on the other hand, carries the potential to develop into a standard tool to predict possible cross-interactions of drug candidates potentially leading to adverse side effects.