Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
Cátedra CONACyT, Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados, IPN, Unidad Mérida, Yucatan 97310, Mexico.
Molecules. 2021 Feb 4;26(4):799. doi: 10.3390/molecules26040799.
Substituted phenylacetic (), phenylpropanoic (), and benzylidenethiazolidine-2,4-dione () derivatives were designed according to a multitarget unified pharmacophore pattern that has shown robust antidiabetic activity. This bioactivity is due to the simultaneous polypharmacological stimulation of receptors PPARα, PPARγ, and GPR40 and the enzyme inhibition of aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP-1B). The nine compounds share the same four pharmacophore elements: an acid moiety, an aromatic ring, a bulky hydrophobic group, and a flexible linker between the latter two elements. Addition and substitution reactions were performed to obtain molecules at moderated yields. In silico pharmacological consensus analysis (PHACA) was conducted to determine their possible modes of action, protein affinities, toxicological activities, and drug-like properties. The results were combined with in vivo assays to evaluate the ability of these compounds to decrease glucose levels in diabetic mice at a 100 mg/kg single dose. Compounds (a phenylpropanoic acid derivative) and (a benzylidenethiazolidine-2,4-dione derivative) ameliorated the hyperglycemic peak in a statically significant manner in a mouse model of type 2 diabetes. Finally, molecular dynamics simulations were executed on the top performing compounds to shed light on their mechanism of action. The simulations showed the flexible nature of the binding pocket of AR, and showed that both compounds remained bound during the simulation time, although not sharing the same binding mode. In conclusion, we designed nine acid bioisosteres with robust in vivo antihyperglycemic activity that were predicted to have favorable pharmacokinetic and toxicological profiles. Together, these findings provide evidence that supports the molecular design we employed, where the unified pharmacophores possess a strong antidiabetic action due to their multitarget activation.
根据多靶点统一药效团模式设计了取代的苯乙酸（）、苯丙酸（）和苯亚甲基噻唑烷-2,4-二酮（）衍生物，该模式显示出强大的抗糖尿病活性。这种生物活性是由于同时多药理学刺激 PPARα、PPARγ 和 GPR40 受体以及醛糖还原酶（AR）和蛋白酪氨酸磷酸酶 1B（PTP-1B）的酶抑制作用。这九个化合物具有相同的四个药效团元素：酸部分、芳环、大的疏水性基团以及后两个元素之间的柔性连接体。通过加成和取代反应以中等收率得到分子。进行了计算机药理学共识分析（PHACA）以确定它们可能的作用方式、蛋白亲和力、毒理学活性和类药性。将结果与体内测定相结合，以评估这些化合物在 100mg/kg 单剂量时降低糖尿病小鼠血糖水平的能力。化合物（苯丙酸衍生物）和（苯亚甲基噻唑烷-2,4-二酮衍生物）以统计学显著的方式改善了 2 型糖尿病小鼠的高血糖峰值。最后，对表现最佳的化合物进行分子动力学模拟，以阐明其作用机制。模拟表明，AR 的结合口袋具有柔性，并且表明尽管两种化合物在模拟过程中都保持结合，但它们并不具有相同的结合模式。总之，我们设计了九个具有强大体内抗高血糖活性的酸生物等排体，预计具有良好的药代动力学和毒理学特性。总之，这些发现提供了支持我们采用的分子设计的证据，其中统一的药效团由于其多靶点激活而具有强大的抗糖尿病作用。
