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.
Highlights
IntroductionThiazolidinediones or glitazones (TZDs) represent established drugs that treat insulin resistance in type 2 diabetes mellitus [1,2], which is a chronic metabolic disorder caused by defects in insulin secretion and insulin action [3]
The docking scores for TGZ ranged from −43 to −58, while the scores for RSG ranged from −37 to −45. These results indicate that the docking scores of TGZ and RSG docked to the PPARγ are higher and less favorable than our proposed targets within the 99.7% confidence interval, implying that these new potential targets may contribute to the understanding of the side effects of both drugs
We focused on two drugs from the thiazolidinedione family, troglitazone, which was the first of its type but was withdrawn from use due to its severe side effects, and rosiglitazone, which was under FDA evaluation for a long time as a potential trigger of cardiovascular diseases [7]
Summary
Thiazolidinediones or glitazones (TZDs) represent established drugs that treat insulin resistance in type 2 diabetes mellitus [1,2], which is a chronic metabolic disorder caused by defects in insulin secretion and insulin action [3]. People with type 2 diabetes mellitus experience a higher risk for developing cardiovascular diseases [4]. TZDs activate peroxisome proliferator-activated receptor gamma (PPARγ), which is a nuclear receptor that regulates the expression of several genes connected with metabolism. PPARγ represents one of the three PPARs, which are nuclear receptors that regulate lipid metabolism and glucose homeostasis, the latter having control over adipocyte differentiation, lipid storage, and insulin sensitization. The primary effects of TZDs through the activation of Pharmaceutics 2021, 13, 315.
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