Mechanistic Insights into Side Effects of Troglitazone and Rosiglitazone Using a Novel Inverse Molecular Docking Protocol

Abstract

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 watch of FDA for a long time due to suspicion, that it causes cardiovascular diseases, such as heart failure and stroke. We applied a novel inverse molecular docking protocol to discern the potential protein targets of both drugs. Troglitazone and rosiglitazone were docked into predicted binding sites of >67,000 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. Certain targets of troglitazone such as 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 the 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. On the other hand, the novel inverse molecular docking protocol 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.

Keywords: CANDOCK; inverse molecular docking; rosiglitazone; side effects; thiazolidinediones; troglitazone.

Figure 1

Chemical structures of troglitazone stereoisomers (a–d). The molecule possesses two chiral centers.

Figure 2

Chemical structures of rosiglitazone enantiomers (a,b). The molecule possesses one chiral center and is present as a racemate in medicinal applications.

Figure 3

Normal distribution fitting graphs of inverse docking scores for (A) troglitazone docked into human targets, (B) rosiglitazone docked into human targets, (C) troglitazone docked into targets from various organisms and (D) rosiglitazone docked into targets from various organisms. 99.7% confidence interval is marked as 3σ and the number of proteins that fit the selected criteria is denoted with N.

Figure 4

Native (blue) and redocked (brown) poses of troglitazone in the cytochrome P450 2C8 protein (light purple). RMSD: 4.51 Å.

Figure 5

Native (blue) and redocked (brown) poses of rosiglitazone in the peroxisome proliferator-activated receptor gamma protein (gray). RMSD: 0.85 Å.

Figure 6

Validations of inverse molecular docking protocol of troglitazone against all human protein targets from the PDB: (a) the receiver operating characteristics (ROC) curve; (b) the predictiveness curve; and (c) the enrichment curve.

Figure 7

Validations of inverse molecular docking protocol of rosiglitazone against all human protein targets from the Protein Date Bank (PDB): (a) the receiver operating characteristics (ROC) curve; (b) the predictiveness curve; and (c) the enrichment curve.