Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to reduce pain, and function by targeting cyclooxygenase (COX) enzymes to inhibit the production of prostaglandins that facilitate inflammation. Since oleocanthal derived from Olea europaea is known to inhibit COX, we sought to characterise novel olive compounds with COX inhibitory activity using in silico techniques. Following on from part 1 of this study which identified 1-oleyltyrosol (1OL) and ligstroside derivative 2 (LG2) with COX inhibitory potential, the mechanisms of COX interactions by these selected compounds were further examined using molecular dynamics (MD) simulations. Classical MD simulations were carried out on COX-1 and COX-2 complexed with 1OL and LG2 to determine the stability and protein backbone fluctuation. Protein dynamics were examined using essential dynamics methods and network analysis, which identified that the N-terminal epidermal growth factor-like domain and membrane bound domains of COX-1 and -2 exhibited altered motions when ligands were bound. Distinct dynamical modules were identified, and that COX-2 inter-residue communications were more sensitive to ligand binding compared to COX-1. The use of various network metrics presents a novel approach in the characterisation of network behaviour of different ligands. It is proposed that inter-residue network metrics provide additional measures of the potential bioactivity of ligands, which may form a useful adjunct to conventional direct predictions of binding affinity, in determining the efficacy of potential small-molecule inhibitors. Overall, this two-part study characterises anti-inflammatory effects of low dosage dietary COX inhibitors, and provides a possible avenue for the development of therapeutics in inflammatory diseases.

非甾体类抗炎药（NSAIDs）通常用于减轻疼痛，并通过靶向环氧合酶（COX）酶起作用来抑制促进炎症的前列腺素的产生。由于已知来自油橄榄的油橄榄素可以抑制COX，因此我们尝试使用计算机模拟来表征具有COX抑制活性的新型橄榄化合物。技术。在本研究的第1部分确定了具有COX抑制潜能的1-油基酪醇（1OL）和糖脂苷衍生物2（LG2）之后，使用分子动力学（MD）模拟进一步研究了这些选定化合物与COX相互作用的机理。在与1OL和LG2络合的COX-1和COX-2上进行了经典的MD模拟，以确定稳定性和蛋白质骨架的波动。使用基本动力学方法和网络分析检查蛋白质动力学，发现当结合配体时，COX-1和-2的N末端表皮生长因子样结构域和膜结合结构域表现出改变的运动。确定了不同的动力学模块，并且与COX-1相比，COX-2残基间通讯对配体结合更敏感。各种网络指标的使用为表征不同配体的网络行为提供了一种新颖的方法。提出残基间网络度量提供了配体潜在生物活性的附加量度，在确定潜在的小分子抑制剂的功效时，其可形成对结合亲和力的常规直接预测的有用辅助。总的来说，这项由两部分组成的研究表征了低剂量饮食COX抑制剂的抗炎作用，并为炎症性疾病治疗药物的开发提供了可能的途径。在确定潜在的小分子抑制剂的功效时，它可能会成为结合亲和力的常规直接预测的有用辅助方法。总的来说，这项由两部分组成的研究表征了低剂量饮食COX抑制剂的抗炎作用，并为炎症性疾病治疗药物的开发提供了可能的途径。在确定潜在的小分子抑制剂的功效时，它可能会成为结合亲和力的常规直接预测的有用辅助方法。总的来说，这项由两部分组成的研究表征了低剂量饮食COX抑制剂的抗炎作用，并为炎症性疾病治疗药物的开发提供了可能的途径。