<i>In silico</i> 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, <i>in silico</i> 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靶向环氧化酶-2（cyclooxygenase-2，COX-2）的非甾体抗炎药（Non-steroidal anti-inflammatory drugs，NSAID）在临床上具有确切疗效。然而此类药物缺乏抗血栓活性，可引发心肌梗死、胃肠道及腹部不适等不良反应，因此亟需开发兼具更优治疗效果与耐受性的新型候选药物。多项近期研究表明，多种地衣是天然抗炎候选药物的宝贵宝库，且这类来源的物质对人体食用安全。药物研发是一项极为复杂且耗时的过程，但计算机模拟（in silico）技术可简化该流程并降低研发成本。为此，本研究针对天然抗炎化合物开展筛选：通过分子对接技术，将412种地衣化合物与人源COX-2酶进行对接，并借助X-Score验证对接得分，随后开展ADMET（吸收-分布-代谢-排泄-毒性）及类药性（Drug-likeness）分析。将筛选得到的6个得分最高的化合物进行分子动力学模拟（Molecular dynamics simulation，MDS），以分析对接所得蛋白-配体复合物的稳定性，并评估蛋白-配体相互作用过程中的波动与构象变化。经过30纳秒的分子动力学模拟后，均方根偏差（RMSD）、回转半径（Rg）及相互作用能量的数值结果显示，与参比药物JMS相比，这些地衣化合物在COX-2活性口袋中具有良好的稳定性。此外，本研究开展了药效团分析，发现地衣化合物与经典抗炎化合物之间存在诸多共同的药效团特征。研究结果表明，这些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，开发出疗效更优、副作用更少的抗炎药物，用于炎症性疾病的治疗。本文由Ramaswamy H. Sarma通讯。