Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab, India.
Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India.
Eur J Med Chem. 2023 Dec 5;261:115826. doi: 10.1016/j.ejmech.2023.115826. Epub 2023 Sep 21.
Diabetes mellitus is a metabolic disorder characterized by elevated blood sugar levels and related complications. This study focuses on harnessing and integrating fragment-based drug design and virtual screening techniques to explore the antidiabetic potential of newly synthesized thiazolidine-2,4-dione derivatives. The research involves the design of novel variations of thiazolidine-2,4-dione compounds by Fragment-Based Drug Design. The screening process involves pharmacophore based virtual screening through docking algorithms, and the identification of newly twelve top-scoring compounds. The molecular docking analysis revealed that compounds SP4e, SP4f showed highest docking scores of -9.082 and -10.345. The binding free energies of the compounds SP4e, SP4f and pioglitazone was found to be -19.9, -16.1 and -13 respectively, calculated using the Prime MM/GBSA approach. The molecular dynamic study validates the docking results. Furthermore, In the Swiss albino mice model, both SP4e and SP4f exhibited significant hypoglycaemic effects, comparable to the reference drug pioglitazone. Furthermore, these compounds demonstrated favorable effects on the lipid profile, reducing total cholesterol, triglycerides, and LDL levels while increasing HDL levels. In mice tissue, the disease control group showed PPAR-γ expression of 4.200 ± 0.24, while compound SP4f displayed higher activation at 7.84 ± 0.431 compared to compound SP4e with an activation of 7.68 ± 0.65. In zebrafish model, SP4e and SP4f showed significant reductions in blood glucose levels and lipid peroxidation, along with increased glutathione levels and catalase activity. These findings highlighted the potential of SP4e and SP4f as antidiabetic agents, warranting further exploration for therapeutic applications. The in vitro study was performed in HEK-2 cell line, the pioglitazone group demonstrated PPAR-γ expression of EC = 575.2, while compound SP4f exhibited enhanced activation at EC = 739.0 in contrast to compound SP4e activation of EC = 826.7.
糖尿病是一种代谢紊乱，其特征是血糖水平升高和相关并发症。本研究旨在利用和整合基于片段的药物设计和虚拟筛选技术，探索新合成的噻唑烷-2,4-二酮衍生物的抗糖尿病潜力。该研究涉及通过基于片段的药物设计设计噻唑烷-2,4-二酮化合物的新型变体。筛选过程包括基于药效团的虚拟筛选，通过对接算法，鉴定出 12 种新的评分最高的化合物。分子对接分析表明，化合物 SP4e、SP4f 的对接评分最高，分别为-9.082 和-10.345。使用 Prime MM/GBSA 方法计算发现，化合物 SP4e、SP4f 和吡格列酮的结合自由能分别为-19.9、-16.1 和-13。分子动力学研究验证了对接结果。此外，在瑞士白化病小鼠模型中，SP4e 和 SP4f 均表现出显著的降血糖作用，与参比药物吡格列酮相当。此外，这些化合物对脂质谱有良好的影响，降低总胆固醇、甘油三酯和 LDL 水平，同时增加 HDL 水平。在小鼠组织中，疾病对照组的 PPAR-γ 表达为 4.200±0.24，而化合物 SP4f 的激活水平为 7.84±0.431，高于化合物 SP4e 的激活水平 7.68±0.65。在斑马鱼模型中，SP4e 和 SP4f 可显著降低血糖水平和脂质过氧化，同时增加谷胱甘肽水平和过氧化氢酶活性。这些发现突显了 SP4e 和 SP4f 作为抗糖尿病药物的潜力，值得进一步探索其治疗应用。体外研究在 HEK-2 细胞系中进行，吡格列酮组的 PPAR-γ 表达 EC=575.2，而化合物 SP4f 的激活 EC=739.0，高于化合物 SP4e 的激活 EC=826.7。
