Kores Katarina, Konc Janez, Bren Urban
Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty for Chemistry and Chemical Technology, University of Maribor, Smetanova 17, SI-2000 Maribor, Slovenia.
Laboratory for Molecular Modeling, Theory Department, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
Pharmaceutics. 2021 Feb 28;13(3):315. doi: 10.3390/pharmaceutics13030315.
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.
噻唑烷二酮类药物可用于治疗2型糖尿病中的胰岛素抵抗。曲格列酮是该类药物中的首个药物，但由于其肝毒性已被美国食品药品监督管理局（FDA）停用。作为替代药物，罗格列酮被研发出来，但由于怀疑其会引发心血管疾病，如心力衰竭和中风，长期以来一直受到FDA的密切关注。我们应用了一种新型的反向分子对接方案来识别这两种药物潜在的蛋白质靶点。将曲格列酮和罗格列酮对接至蛋白质数据库中>67,000个蛋白质结构的预测结合位点并进行研究。识别出了几种曲格列酮和罗格列酮成功对接的新潜在蛋白质靶点。研究重点放在人类蛋白质上，以便解释或提出现有或新的潜在副作用。确定了曲格列酮的某些靶点，如3-氧代-5-β-甾体4-脱氢酶、中性粒细胞胶原酶、基质溶解素-1和极长链酰基辅酶A脱氢酶（VLCAD），这些靶点可以解释其肝毒性，另外一些靶点表明其应用可能导致癌症的治疗/发展。罗格列酮的研究结果显示其与基质金属蛋白酶家族成员相互作用，这可能导致癌症和神经退行性疾病。罗格列酮令人担忧的心血管副作用也可以得到解释。我们坚信，我们的研究结果加深了对这两种药物副作用机制的理解，并且随着进一步的开发和研究，甚至可能有助于将副作用降至最低。另一方面，这种新型反向分子对接方案有可能发展成为一种标准工具，用于预测可能导致不良副作用的候选药物之间的交叉相互作用。
