Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India.
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India.
Bioorg Chem. 2021 Mar;108:104556. doi: 10.1016/j.bioorg.2020.104556. Epub 2020 Dec 15.
Herein, a quantum mechanics/molecular mechanics (QM/MM) based biotransformation study was performed on synthetically feasible mutual-prodrugs of epalrestat which have been identified from an in-house database developed by us. These prodrugs were submitted to quantum polarized ligand docking (QPLD) with the CES1 enzyme followed by MM-GBSA calculation. Electronic aspects of transition state of these prodrugs were also considered to study the catalytic process through density functional theory (DFT). ADMET analysis of prodrugs was then carried out to assess the drug-likeness. On the basis of in-silico results, the best five prodrugs were synthesized and further evaluated for their neuroprotective and nephroprotective potential in high-fat diet-streptozotocin (HFD-STZ) induced diabetes in rat model. Clinically relevant molecular manifestations of diabetic complications (DC) including aldose reductase (ALR2) activity and oxidative stress markers such as reduced glutathione (GSH), catalase (CAT), and thiobarbituric acid reactive substances (TBARS) were determined in blood plasma as well as tissues of the brain and kidneys. The histopathological examination of these organs was also carried out to see the improvement in structural deformities caused due to neuropathy and nephropathy. Finally, in-vivo pharmacokinetic study was performed for the best two prodrugs to assess the improvement in biopharmaceutical attributes of parent drugs. Overall, EP-G-MFA and EP-MFA have significantly reduced the hyperglycemia-induced ALR2 activity, levels of oxidative stress markers, and manifested about a two-fold increase in the biological half-life (T) of parent drugs. The overall findings of this study suggest that methyl ferulate conjugated prodrugs of epalrestat may be considered as potential protective agents in diabetic neuropathy and nephropathy.
在此，我们对一种从我们内部数据库中鉴定出的、具有合成可行性的依帕司他的前药进行了基于量子力学/分子力学（QM/MM）的生物转化研究。这些前药与 CES1 酶进行了量子极化配体对接（QPLD），并进行了 MM-GBSA 计算。我们还考虑了这些前药过渡态的电子方面，以通过密度泛函理论（DFT）研究催化过程。然后对前药进行了 ADMET 分析，以评估其类药性。根据计算机模拟结果，合成了最好的五种前药，并在高脂肪饮食-链脲佐菌素（HFD-STZ）诱导的糖尿病大鼠模型中进一步评估了它们的神经保护和肾保护潜力。在血液血浆以及大脑和肾脏组织中测定了与临床相关的糖尿病并发症（DC）分子表现，包括醛糖还原酶（ALR2）活性和氧化应激标志物，如还原型谷胱甘肽（GSH）、过氧化氢酶（CAT）和硫代巴比妥酸反应物质（TBARS）。还对这些器官进行了组织病理学检查，以观察由于神经病变和肾病引起的结构畸形的改善。最后，对两种最好的前药进行了体内药代动力学研究，以评估母体药物生物制药特性的改善。总的来说，EP-G-MFA 和 EP-MFA 显著降低了高血糖诱导的 ALR2 活性、氧化应激标志物水平，并使母体药物的生物半衰期（T）增加了约两倍。这项研究的总体结果表明，依帕司他的甲基阿魏酸共轭前药可能被视为糖尿病神经病变和肾病的潜在保护剂。
