Faculty of Chemistry, University of Warsaw, Warsaw, Poland.
Department of Pharmacognosy, Faculty of Pharmacy, Poznan University of Medical Sciences, Poznan, Poland.
PLoS One. 2019 Jan 16;14(1):e0208892. doi: 10.1371/journal.pone.0208892. eCollection 2019.
A disturbance of glucose homeostasis leading to type 2 diabetes mellitus (T2DM) is one of the severe side effects that may occur during a prolonged use of many drugs currently available on the market. In this manuscript we describe the most common cases of drug-induced T2DM, discuss available pharmacotherapies and propose new ones. Among various pharmacotherapies of T2DM, incretin therapies have recently focused attention due to the newly determined crystal structure of incretin hormone receptor GLP1R. Incretin hormone receptors: GLP1R and GIPR together with the glucagon receptor GCGR regulate food intake and insulin and glucose secretion. Our study showed that incretin hormone receptors, named also gut hormone receptors as they are expressed in the gastrointestinal tract, could potentially act as unintended targets (off-targets) for orally administrated drugs. Such off-target interactions, depending on their effect on the receptor (stimulation or inhibition), could be beneficial, like in the case of incretin mimetics, or unwanted if they cause, e.g., decreased insulin secretion. In this in silico study we examined which well-known pharmaceuticals could potentially interact with gut hormone receptors in the off-target way. We observed that drugs with the strongest binding affinity for gut hormone receptors were also reported in the medical information resources as the least disturbing the glucose homeostasis among all drugs in their class. We suggested that those strongly binding molecules could potentially stimulate GIPR and GLP1R and/or inhibit GCGR which could lead to increased insulin secretion and decreased hepatic glucose production. Such positive effect on the glucose homeostasis could compensate for other, adverse effects of pharmacotherapy which lead to drug-induced T2DM. In addition, we also described several top hits as potential substitutes of peptidic incretin mimetics which were discovered in the drug repositioning screen using gut hormone receptors structures against the ZINC15 compounds subset.
葡萄糖稳态紊乱导致 2 型糖尿病（T2DM）是许多目前市场上可用药物长期使用可能出现的严重副作用之一。在本文中，我们描述了最常见的药物引起的 T2DM 病例，讨论了可用的药物治疗方法并提出了新的方法。在各种 T2DM 的药物治疗中，由于肠降血糖素激素受体 GLP1R 的新确定晶体结构，肠降血糖素激素治疗最近引起了关注。肠降血糖素激素受体：GLP1R 和 GIPR 与胰高血糖素受体 GCGR 一起调节食物摄入以及胰岛素和葡萄糖分泌。我们的研究表明，肠降血糖素激素受体，也称为胃肠激素受体，因为它们在胃肠道中表达，可能作为意外的靶标（非靶标）发挥作用口服药物。这种非靶标相互作用，取决于其对受体的影响（刺激或抑制），可能是有益的，例如肠降血糖素类似物，或者是有害的，例如降低胰岛素分泌。在这项计算机研究中，我们研究了哪些知名药物可能以非靶标方式与胃肠激素受体相互作用。我们观察到，与胃肠激素受体具有最强结合亲和力的药物也在医学信息资源中被报道为与其类别的所有药物相比，对葡萄糖稳态干扰最小。我们推测，那些与受体结合紧密的分子可能会刺激 GIPR 和 GLP1R 并/或抑制 GCGR，从而导致胰岛素分泌增加和肝葡萄糖产生减少。这种对葡萄糖稳态的积极影响可以补偿药物治疗的其他不良影响，从而导致药物引起的 T2DM。此外，我们还描述了几种作为潜在替代物的热门候选药物，这些药物是在使用胃肠激素受体结构针对 ZINC15 化合物子集进行的药物重新定位筛选中发现的。
