Akter Bakul, Uddin Md Sohorab, Islam Mohammad Rashedul, Ahamed Kutub Uddin, Aktar Most Nazmin, Hossain Mohammed Kamrul, Salamatullah Ahmad Mohammad, Bourhia Mouhammed
Department of Pharmacy, Faculty of Biological Sciences, University of Chittagong, Chittagong, Bangladesh.
Pharmaceutical Sciences Research Division, BCSIR Dhaka Laboratories, Bangladesh Council of Scientific and Industrial Research (BCSIR), Dhaka, Bangladesh.
Cell Biochem Biophys. 2025 Mar;83(1):1057-1070. doi: 10.1007/s12013-024-01540-1. Epub 2024 Oct 8.
Type 2 diabetes mellitus (T2DM) is usually depicted by relative insulin deficiency, raised blood glucose levels, and the predominant risk factor, insulin resistance. Hence, the development of insulin sensitizer drugs targeting PPAR-γ receptors has expanded enormous interest as an attractive choice for T2DM treatment. Thiazolidinediones (TZD) enhance insulin sensitivity either by directly functioning on gene transcription of the PPARγ receptor related to glucose homeostasis or by systemic sensitization of insulin and, therefore, improved hyperglycemia in a wide range of patients. However, severe complications and adverse effects of TZDs necessitate the development of an efficacious and reliable insulin sensitizer from alternative resources. On the contrary, Nature is a rich source of anticipated effective and safer medicine; more than fifty percent of drugs on the market are developed from natural products. Hence, searching for a new PPAR-γ agonist from bioactive secondary compounds of medicinal plants along with greater efficacy and safety is a recognized and consistent tactic for developing novel antidiabetic agents. Pulicaria jaubertii is a fragrant perennial aromatic plant with anti-inflammatory, antidiabetic, antimicrobial, antimalarial, and insecticidal properties. The current study was designed to use a computer-aided drug design to explore the best antidiabetic compounds from P. jaubertii. Herein, the molecular docking study of 80 investigated ligands against the PPAR-γ receptor identifies the highest docking score for five ligands ranging from -8.9 kcal/mol to 8.0 kcal/mol, which is also more significant than the standard drug pioglitazone (-7.7 kcal/mol) determined by the PyRx 8.0 virtual screening software. GLN286, CYS285, SER289, TYR473, MET364, ARG288, ILE341, and LEU333 residues are found to be significant contributors to the non-bonded interaction between ligands and receptors. Molecular electrostatic potential (MEP), DFT, molecular orbital (MO), ADMET, and toxicological analyses were performed on the selected five high-scored ligands of P. jaubertii. Results documented that all investigated ligands, especially L4, show considerably excellent profiles in molecular docking, MEP, DFT, MO, ADMET, and toxicological predictions, suggesting our drug-designing approaches may contribute to the development of a novel antidiabetic drug for the treatment of T2DM from natural resources.
2型糖尿病（T2DM）通常表现为相对胰岛素缺乏、血糖水平升高以及主要危险因素胰岛素抵抗。因此，开发针对PPAR-γ受体的胰岛素增敏剂药物作为T2DM治疗的一种有吸引力的选择引起了广泛关注。噻唑烷二酮类（TZD）通过直接作用于与葡萄糖稳态相关的PPARγ受体的基因转录或通过胰岛素的全身增敏作用来增强胰岛素敏感性，从而在广泛的患者中改善高血糖。然而，TZD的严重并发症和不良反应使得有必要从其他来源开发一种有效且可靠的胰岛素增敏剂。相反，自然界是预期有效且更安全药物的丰富来源；市场上超过50%的药物是由天然产物开发而来。因此，从药用植物的生物活性次生化合物中寻找一种新的PPAR-γ激动剂，同时具有更高的疗效和安全性，是开发新型抗糖尿病药物的一种公认且一致的策略。普氏旋覆花是一种多年生芳香植物，具有抗炎、抗糖尿病、抗菌、抗疟疾和杀虫特性。本研究旨在利用计算机辅助药物设计从普氏旋覆花中探索最佳抗糖尿病化合物。在此，对80种研究配体与PPAR-γ受体进行分子对接研究，确定了5种配体的最高对接分数，范围为-8.9 kcal/mol至8.0 kcal/mol，这也比PyRx 8.0虚拟筛选软件确定的标准药物吡格列酮（-7.7 kcal/mol）更显著。发现GLN286、CYS285、SER289、TYR473、MET364、ARG288、ILE341和LEU333残基是配体与受体之间非键相互作用的重要贡献者。对普氏旋覆花选定的5种高分配体进行了分子静电势（MEP）、密度泛函理论（DFT）、分子轨道（MO）、药物代谢动力学（ADMET）和毒理学分析。结果表明，所有研究的配体，尤其是L4，在分子对接、MEP、DFT、MO、ADMET和毒理学预测方面均表现出相当优异的特性，表明我们的药物设计方法可能有助于从自然资源中开发一种用于治疗T2DM的新型抗糖尿病药物。
