Modanwal Shristi, Maurya Akhilesh Kumar, Mulpuru Viswajit, Mishra Nidhi
Department of Applied Sciences, Indian Institute of Information of Technology Allahabad, Prayagraj, India.
Indian Institute of Technology Bombay, Mumbai, India.
Mol Divers. 2025 Jun;29(3):2499-2516. doi: 10.1007/s11030-024-11005-5. Epub 2024 Oct 11.
Obesity is widely recognized as a major public health issue and is one of the leading causes of death worldwide. Overweight and obesity are prominent lifestyle ailments that not only give rise to additional health issues but also play a role in the development of other chronic diseases, such as cancer, diabetes, metabolic syndrome, and cardiovascular diseases. Orlistat is now the only pharmaceutical drug for the management of obesity. However, prolonged use of orlistat has been associated with detrimental consequences, hence necessitating the development of a new drug with reduced or no adverse reactions. Pancreatic Lipase is a critical enzyme in lipid metabolism. Using naturally occurring compounds as PL inhibitors has garnered significant attention because of their diverse structure and low toxicity. The present work investigates the inhibitory action of flavonoids on PL using in silico and in vitro methods. Thirteen flavonoid derivatives and orlistat were docked with PL. The ADME properties of the flavonoid derivatives were studied, and most of the compounds are in admire range. The stability of the best-docked complexes was checked by REMD. The in silico study demonstrated favorable inhibitory activity of flavonoids compared to orlistat. Consequently, an enzyme inhibitory experiment was conducted to authenticate the in silico results. The lipase inhibitory activity was assessed by using p-nitrophenyl butyrate as the substrate. Kaempferol exhibited significant inhibitory activity against PL, as shown by its IC value of 72.7 ± 3 µM. This study proposed a natural drug candidate with promising inhibitory efficacy against PL for obesity.
肥胖被广泛认为是一个主要的公共卫生问题，是全球主要死因之一。超重和肥胖是突出的生活方式疾病，不仅会引发其他健康问题，还在其他慢性疾病（如癌症、糖尿病、代谢综合征和心血管疾病）的发展中起作用。奥利司他是目前唯一用于治疗肥胖症的药物。然而，长期使用奥利司他会带来不良后果，因此需要开发一种不良反应减少或无不良反应的新药。胰脂肪酶是脂质代谢中的一种关键酶。使用天然存在的化合物作为胰脂肪酶抑制剂因其结构多样且毒性低而备受关注。本研究使用计算机模拟和体外方法研究黄酮类化合物对胰脂肪酶的抑制作用。13种黄酮类衍生物和奥利司他与胰脂肪酶进行对接。研究了黄酮类衍生物的吸收、分布、代谢和排泄（ADME）特性，大多数化合物处于理想范围内。通过 replica exchange molecular dynamics（REMD）检查最佳对接复合物的稳定性。计算机模拟研究表明，与奥利司他相比，黄酮类化合物具有良好的抑制活性。因此，进行了酶抑制实验以验证计算机模拟结果。以对硝基苯基丁酸酯为底物评估脂肪酶抑制活性。山奈酚对胰脂肪酶表现出显著的抑制活性，其IC值为72.7±3µM。本研究提出了一种对胰脂肪酶具有有望的抑制功效用于治疗肥胖症的天然药物候选物。
