Exploring molecular docking with MM-GBSA and molecular dynamics simulation to predict potent inhibitors of cyclooxygenase (COX-2) enzyme from terpenoid-based active principles of <i>Zingiber</i> species

Cyclooxygenase 2 (COX-2), the key enzyme involved in prostaglandin (PGs) production, is known to take part in inflammatory and immune responses. Though COX-2 inhibitors are therapeutically effective anti-inflammatory drugs, they deficit anti-thrombotic activity thus leading to increased cardiovascular diseases. Therefore, COX-2 inhibitors with improved therapeutic efficacy and tolerance are still needed. In recent years, traditional medicine systems have paid attention to the essential oil of genus <i>Zingiber</i>, particularly for the treatment of various inflammatory illnesses, with lesser side effects. Thus, the present study aims to explore the anti-inflammatory activity of <i>Zingiber</i> essential oil through computational-biology approaches. In this regard, virtual screening, molecular docking, and simulations were carried out on 53 compounds derived from the essential oil of <i>Zingiber</i> species in order to provide mechanistic insights into COX-2 inhibition and identify the most actively potent anti-inflammatory compounds. Among all the docked ligands, epi-cubenol, δ-cadinene, γ-eudesmol, cubenol, and α-terpineol were found to be powerful bioactive compounds with an increased binding affinity towards COX-2 along with favorable physiochemical properties. Additionally, MD simulation in DPPC lipid bilayers was studied to examine the intrinsic dynamics and adaptability of the chosen ligands and COX-2-complexes. The findings showed that the selected five components interacted steadily with the COX-2 active site residues throughout the simulation via different bondings. The integrative-computational approach showed that the identified natural compounds may be taken into further consideration for potential <i>in vitro</i> and <i>in vivo</i> evaluation as COX-2 inhibitors, which would lead to the development of more potent and efficient anti-inflammatory drugs. Communicated by Ramaswamy H. Sarma环氧合酶2（Cyclooxygenase 2, COX-2）是参与前列腺素（prostaglandin, PGs）合成的关键酶，已知其在炎症与免疫应答过程中发挥重要作用。尽管COX-2抑制剂是具有临床治疗价值的抗炎药物，但这类药物缺乏抗血栓活性，因此会提升心血管疾病的发病风险。故而，研发兼具更优治疗效果与耐受性的COX-2抑制剂仍是当前亟待解决的需求。近年来，传统医药体系对姜属（Zingiber）植物精油愈发关注，因其在治疗各类炎症性疾病时副作用相对轻微。鉴于此，本研究旨在通过计算生物学方法探究姜属植物精油的抗炎活性。据此，本研究对姜属植物精油中的53种化合物开展了虚拟筛选、分子对接与分子动力学模拟实验，以期阐明COX-2抑制的分子机制，并筛选出抗炎活性最强的候选化合物。在所有对接配体中，表古巴烯醇（epi-cubenol）、δ-杜松烯（δ-cadinene）、γ-桉叶醇（γ-eudesmol）、古巴烯醇（cubenol）与α-松油醇（α-terpineol）被证实为强效生物活性化合物：它们对COX-2具有较高的结合亲和力，同时具备良好的理化性质。此外，本研究还在二棕榈酰磷脂酰胆碱（DPPC）脂质双层体系中开展了分子动力学模拟，以考察所选配体与COX-2复合物的内在动力学特性与结构适配性。实验结果表明，在整个模拟周期内，上述五种筛选得到的成分可通过多种键合方式与COX-2活性位点残基稳定结合。综合计算生物学分析结果显示，本次鉴定得到的天然化合物可作为潜在的COX-2抑制剂，进一步开展体外（in vitro）与体内（in vivo）评价，有望助力开发出活性更强、疗效更优的新一代抗炎药物。本文由Ramaswamy H. Sarma转交刊发。