In silico screening of anti-inflammatory compounds from Lichen by targeting cyclooxygenase-2

Non-steroidal anti-inflammatory drugs (NSAID) targeting cyclooxygenase-2 are clinically effective. However, they lack anti-thrombotic activity resulting in incidences of adverse effects like myocardial infarction, gastrointestinal and abdominal discomfort which necessitate for discovering new drug candidates with improved therapeutic effects and tolerability. Various recent researches have suggested that many lichens offer a vast reservoir for anti-inflammatory drug candidates which are natural as well as safe for human consumption. Drug discovery is a very complex and time-consuming process; however, in silico techniques can make this process simple and economic. Hence to find out natural anti-inflammatory compounds, we have carried out the virtual screening of 412 lichen compounds by molecular docking with human Cox-2 enzyme and validated the docking score by X-Score followed by ADMET and Drug-likeness analysis. The resulting 6 top-scored compounds were subjected to Molecular dynamics simulation (MDS) to analyze the stability of docked protein-ligand complex, to assess the fluctuation and conformational changes during protein-ligand interaction. The values of RMSD, Rg, and interaction energy after 30 ns of MDS revealed the good stability of these Lichen compounds in the active site pocket of Cox-2 in compare to reference, JMS. Additionally, we have done the pharmacophore analysis which found many common pharmacophore features between Lichen compounds and well known anti-inflammatory compounds. Our result shows that these lichen compounds are potential anti-inflammatory candidates and could be further modified and evaluated to develop more effective anti-inflammatory drugs with fewer side effects for the treatment of inflammatory diseases. Communicated by Ramaswamy H. Sarma靶向环氧合酶-2（cyclooxygenase-2）的非甾体抗炎药（Non-steroidal anti-inflammatory drugs, NSAID）临床疗效确切，但该类药物缺乏抗血栓活性，可引发心肌梗死、胃肠道与腹部不适等不良反应，因此亟需开发治疗效果更优、耐受性更佳的新型候选药物。近年来多项研究表明，地衣是一类可供人类食用的天然抗炎候选药物的巨大宝库。药物研发过程极为复杂且耗时漫长，而虚拟实验技术（in silico techniques）可简化该流程并降低研发成本。为此，本研究针对412种地衣来源化合物，通过与人类环氧合酶-2（Cox-2）酶进行分子对接（molecular docking）开展虚拟筛选（virtual screening），并通过X-Score验证对接打分，随后开展ADMET（吸收、分布、代谢、排泄、毒性）分析与类药性（Drug-likeness）分析。选取打分排名前6的化合物开展分子动力学模拟（Molecular dynamics simulation, MDS），以分析对接得到的蛋白质-配体复合物的稳定性，评估蛋白-配体相互作用过程中的波动与构象变化。经30纳秒分子动力学模拟后，均方根偏差（Root Mean Square Deviation, RMSD）、回转半径（Radius of Gyration, Rg）及相互作用能的数值结果显示，相较于对照物JMS，此类地衣化合物在Cox-2的活性位点口袋中具有良好的稳定性。此外，本研究还开展了药效团分析（pharmacophore analysis），发现地衣来源化合物与已知抗炎化合物间存在诸多共同药效团特征。本研究结果表明，此类地衣化合物是极具潜力的抗炎候选药物，可通过进一步修饰与评价，开发出副作用更少、疗效更优的抗炎药物，用于炎症性疾病的治疗。本文由Ramaswamy H. Sarma提交。