Faculty of Industrial Sciences and Technology, Universiti Malaysia Pahang Al-Sultan Abdullah, Lebuhraya Persiaran Tun Khalil Yaakob, Kuantan, Pahang, Malaysia; Centre for Bio-aromatic Research, Universiti Malaysia Pahang Al-Sultan Abdullah, Lebuhraya Persiaran Tun Khalil Yaakob, Kuantan, Pahang, Malaysia.
Institute of Food Science and Technology, Bangladesh Council of Scientific and Industrial Research, Dhaka 1205, Bangladesh.
Comput Biol Chem. 2024 Oct;112:108149. doi: 10.1016/j.compbiolchem.2024.108149. Epub 2024 Jul 14.
Bladder cancer (BC) is the 10th most common tumour with a high incidence and recurrence rate worldwide; however, the current therapies present limitations as, regularly, not all patients benefit from treatment. Therefore, the search for new, active marine phenolic acids with anti-tumour properties is imperative. In this study, we subjected marine phenolic acids to in silico investigations such as network pharmacology, molecular docking, and molecular dynamics simulation (MD) to identify a plausible pathway and the lead compound that inhibits BC. According to the network pharmacology analysis, eight hub genes (PLAU, MMP2, ITGB3, MAPK1, PTPN11, ESR1, TLR4, MMP9) were found and linked to the enrichment of hsa05205: proteoglycans in cancer, and four hub genes (MMP1, MMP2, MAPK1, MMP9) were involved in the enrichment of hsa05219: BC. Subsequently, molecular docking studies showed that the marine phenolic acids exhibit a strong binding affinity for the target protein, matrix metalloproteinase-9 (MPP9). Among these 14 marine phenolic acids, chicoric acid showed the highest binding affinity of -67.1445 kcal/mol and formed hydrogen bonds with the residues of Ala189, Gln227, Leu188, His226, Ala242, Arg249, Ala191, and Gly186 in the active site of the MPP9 protein. Then, molecular dynamics simulation revealed that chicoric acid formed a stable protein-ligand complex with RMSD and RMSF values of 0.72 nm and 0.53 nm, respectively. Furthermore, the PCA method was employed to understand the dynamical behaviour in the conformational space of MPP9 protein bound to chicoric acid, and the results showed the good conformational space behaviour of MPP9 protein. Moreover, chicoric acid showed a free binding energy value of -32.62 kcal/mol, which indicated it could be a BC inhibitor. Overall, chicoric acid demonstrated potential anti-BC activity through MPP9 protein inhibition.
膀胱癌 (BC) 是全球第 10 大常见肿瘤，发病率和复发率都很高；然而，目前的治疗方法存在局限性，因为并非所有患者都能从治疗中受益。因此，寻找具有抗肿瘤活性的新型海洋酚酸是当务之急。在这项研究中，我们对海洋酚酸进行了网络药理学、分子对接和分子动力学模拟 (MD) 等方面的研究，以确定一种可能的途径和抑制 BC 的先导化合物。根据网络药理学分析，发现了 8 个枢纽基因 (PLAU、MMP2、ITGB3、MAPK1、PTPN11、ESR1、TLR4、MMP9)，并与 hsa05205 的富集相关：癌症中的糖蛋白，而 4 个枢纽基因 (MMP1、MMP2、MAPK1、MMP9) 参与了 hsa05219 的富集：膀胱癌。随后，分子对接研究表明，海洋酚酸对靶蛋白基质金属蛋白酶-9 (MMP9) 具有很强的结合亲和力。在这 14 种海洋酚酸中，菊苣酸表现出最强的结合亲和力-67.1445 kcal/mol，并与 MMP9 蛋白活性位点残基 Ala189、Gln227、Leu188、His226、Ala242、Arg249、Ala191 和 Gly186 形成氢键。然后，分子动力学模拟表明，菊苣酸与 MMP9 蛋白形成了一个稳定的蛋白-配体复合物，RMSD 和 RMSF 值分别为 0.72nm 和 0.53nm。此外，采用 PCA 方法来理解 MMP9 蛋白与菊苣酸结合时构象空间中的动力学行为，结果表明 MMP9 蛋白具有良好的构象空间行为。此外，菊苣酸显示出自由结合能值为-32.62 kcal/mol，这表明它可能是一种膀胱癌抑制剂。总的来说，菊苣酸通过抑制 MMP9 蛋白表现出潜在的抗膀胱癌活性。
