Division of Veterinary Biochemistry, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST-K, Shuhama, Alusteng, Srinagar 190006, India.
Genome Engineering and Societal Biotechnology Lab., Division of Plant Biotechnology, SKUAST-K, Shalimar, Srinagar 190006, India.
Medicina (Kaunas). 2023 Nov 22;59(12):2058. doi: 10.3390/medicina59122058.
: Cyclooxygenase-2 (COX-2) is mostly linked to inflammation and has been validated as a molecular target for treating inflammatory diseases. The present study aimed to identify novel compounds that could inhibit COX-2, which is associated with various diseases including inflammation, and in such a scenario, plant-derived biomolecules have been considered as attractive candidates. : In the present study, physiochemical properties and toxicity of natural compounds/drugs were determined by SWISSADME and ProTox-II. In the present study, the molecular docking binding features of saffron derivatives (crocetin, picrocrocin, quercetin, safranal, crocin, rutin, and dimethylcrocetin) against human COX-2 protein were assessed. Moreover, protein-protein interactions, topographic properties, gene enrichment analysis and molecular dynamics simulation were also determined. : The present study revealed that picrocrocin showed the highest binding affinity of -8.1 kcal/mol when docked against the COX-2 protein. PROCHECK analysis revealed that 90.3% of the protein residues were found in the most favored region. Compartmentalized Protein-Protein Interaction identified 90 interactions with an average interaction score of 0.62, and the highest localization score of 0.99 found in secretory pathways. The Computed Atlas of Surface Topography of Proteins was used to identify binding pockets and important residues that could serve as drug targets. Use of WEBnmα revealed protein dynamics by using normal mode analysis. Ligand and Receptor Dynamics used the Molecular Generalized Born Surface Area approach to determine the binding free energy of the protein. Gene enrichment analysis revealed that ovarian steroidogenesis, was the most significant enrichment pathway. Molecular dynamic simulations were executed for the best docked (COX-2-picrocrocin) complex, and the results displayed conformational alterations with more pronounced surface residue fluctuations in COX-2 with loss of the intra-protein hydrogen bonding network. The direct interaction of picrocrocin with various crucial amino-acid residues like GLN, TYR, HIS, ASN, and TRP causes modifications in these residues, which ultimately attenuates the activity of COX-2 protein. : The present study revealed that picrocrocin was the most effective biomolecule and could be repurposed via computational approaches. However, various in vivo and in vitro observations are still needed.
环氧化酶-2（COX-2）主要与炎症有关，已被验证为治疗炎症性疾病的分子靶标。本研究旨在鉴定新型化合物，以抑制与各种疾病相关的 COX-2，在这种情况下，植物衍生的生物分子被认为是有吸引力的候选物。在本研究中，通过 SWISSADME 和 ProTox-II 确定了天然化合物/药物的物理化学性质和毒性。在本研究中，评估了藏红花衍生物（西红花酸、西红花苦苷、槲皮素、柠檬醛、藏红花酸、芦丁和二甲基西红花酸）与人 COX-2 蛋白的分子对接结合特征。此外，还进行了蛋白质-蛋白质相互作用、地形特性、基因富集分析和分子动力学模拟。本研究表明，当与 COX-2 蛋白对接时，西红花苦苷表现出最高的结合亲和力为-8.1 kcal/mol。PROCHECK 分析表明，90.3%的蛋白质残基位于最有利区域。分区蛋白-蛋白相互作用确定了 90 个相互作用，平均相互作用得分为 0.62，最高定位得分为 0.99，存在于分泌途径中。使用 Computed Atlas of Surface Topography of Proteins 识别结合口袋和重要残基，这些残基可作为药物靶点。使用 WEBnmα 通过正常模式分析显示蛋白质动力学。配体和受体动力学使用分子广义 Born 表面面积方法来确定蛋白质的结合自由能。基因富集分析表明，卵巢类固醇生成是最重要的富集途径。对最佳对接（COX-2-西红花苦苷）复合物进行分子动力学模拟，结果显示 COX-2 中构象发生改变，表面残基波动更为明显，蛋白质内氢键网络丢失。西红花苦苷与 GLN、TYR、HIS、ASN 和 TRP 等各种关键氨基酸残基的直接相互作用导致这些残基发生变化，最终降低 COX-2 蛋白的活性。本研究表明，西红花苦苷是最有效的生物分子，可以通过计算方法重新用于治疗。然而，仍需要进行各种体内和体外观察。
