Massaga Caroline, Paul Lucas, Kwiyukwa Lucas P, Vianney John-Mary, Chacha Musa, Raymond Jofrey
School of Life Science and Bioengineering, The Nelson Mandela African Institution of Science and Technology, P.O. Box 447, Arusha, Tanzania.
Department of Chemistry, Dar es Salaam University College of Education, P.O. Box 2329, Dar es Salaam, Tanzania.
Free Radic Biol Med. 2025 Feb 1;227:508-520. doi: 10.1016/j.freeradbiomed.2024.12.003. Epub 2024 Dec 4.
Urolithin A, an active precursor derived from the metabolism of ellagitanins in rats and humans, is known for its potential health benefits, including stimulating mitophagy and promoting muscular skeletal function. While experimental studies have demonstrated Urolithin A's potential to enhance cellular health, the detailed molecular interactions through which Urolithin A exerts its effects are not fully elucidated. In this study, we investigated the anti-inflammatory, antioxidation and neuroprotective abilities of Urolithin A in selected targets using molecular docking and molecular dynamics simulation methods. Molecular docking studies revealed the strong affinity for receptors involved in inflammation activities, including human p38 MAP kinase (4DLI) with -10.1 kcal/mol interacting with SER252, LYS249, and ASP294 residues. The binding energy in the 5KIR target was -8.6 kcal/mol, interacting with GLN203 through hydrogen bond, and lastly, 1A9U with an affinity of -6.8 with no hydrogen bond formed with Urolithin A and interacts with van der Waals interactions. In oxidant targets, the influence of Urolithin was observed in 1OG5 with -7.9 kcal/mol interacting with GLN185, PHE447. For the 1M17 target, the binding affinity was -7.7 kcal/mol interacting with THR95 residue and 1ZXM target at -7.4 kcal/mol interacting with TYR36, TYR216, and LEU234 residues. The neuroprotective ability of urolithin A was observed in selected targets for acetylcholinesterase; the binding energy was -9.7 kcal/mol interacting with van der Waals and π interactions; for the 1GQR target, the binding energy was -9.9 kcal/mol interacting with van der Waals and π interactions and for β-amylase (1iyt) the binding energy was -5.5 forming hydrogen bond with SER8, GLN15 residues. Molecular Dynamics simulations at 100 ns of Urolithin A compared with reference 4DLI. The Urolithin A-4DLI complex exhibited greater stability than the reference receptor, as confirmed by RMSD, RMSF, Radius of Gyration, Hydrogen bond, and SASA analyses.
尿石素A是一种在大鼠和人类中由鞣花单宁代谢产生的活性前体，因其潜在的健康益处而闻名，包括刺激线粒体自噬和促进肌肉骨骼功能。虽然实验研究已经证明尿石素A具有增强细胞健康的潜力，但其发挥作用的详细分子相互作用尚未完全阐明。在本研究中，我们使用分子对接和分子动力学模拟方法研究了尿石素A在选定靶点中的抗炎、抗氧化和神经保护能力。分子对接研究表明，尿石素A对参与炎症活动的受体具有很强的亲和力，包括与SER252、LYS249和ASP294残基相互作用的人p38丝裂原活化蛋白激酶（4DLI），结合能为-10.1 kcal/mol。在5KIR靶点中的结合能为-8.6 kcal/mol，通过氢键与GLN203相互作用，最后，1A9U的亲和力为-6.8，与尿石素A未形成氢键，通过范德华相互作用相互作用。在氧化靶点中，在1OG5中观察到尿石素的影响，结合能为-7.9 kcal/mol，与GLN185、PHE447相互作用。对于1M17靶点，结合亲和力为-7.7 kcal/mol，与THR95残基相互作用，1ZXM靶点的结合亲和力为-7.4 kcal/mol，与TYR36、TYR216和LEU234残基相互作用。在选定的乙酰胆碱酯酶靶点中观察到尿石素A的神经保护能力；结合能为-9.7 kcal/mol，通过范德华和π相互作用相互作用；对于1GQR靶点，结合能为-9.9 kcal/mol，通过范德华和π相互作用相互作用，对于β-淀粉酶（1iyt），结合能为-5.5，与SER8、GLN15残基形成氢键。将尿石素A与参考4DLI进行100 ns的分子动力学模拟。通过均方根偏差（RMSD）、均方根波动（RMSF）、回转半径、氢键和溶剂可及表面积（SASA）分析证实，尿石素A-4DLI复合物比参考受体表现出更高的稳定性。
