Introduction: Rheumatoid Arthritis [RA] is an autoimmune disease that can cause chronic inflammation of the joints. Human DiHydroOrotate DeHydrogenase [DHODH] is a clinically validated drug target for the treatment of Rheumatoid Arthritis. DHODH inhibition results in beneficial immunosuppressant and anti-proliferative effects.

Materials and Methods: Leflunomide [LEF] and Brequinar Sodium [BREQ], drugs used in the treatment of RA, suppresses the immune cells responsible for inflammation but has several side-effects, most predominant being symptomatic liver damage and toxicity. An existing scaffold based on structural analogies with LEF and BREQ was used to screen out potent inhibitors of DHODH, in ZINC Database using 2D binary fingerprint. 10 structures similar to the scaffold were shortlisted due to their Tanimoto similarity coefficient. Selected structures were docked using the tools AutoDock, Ligand fit and iGEMDOCK with target human DHODH. High scoring compounds having similar interactions as that of scaffold were checked to evaluate their Drug-Likeliness.

Results: The five shortlisted compounds were then subjected to Molecular Dynamics Simulation studies for 50ns using GROMACS. Measures of structural similarity based on 2D Fingerprint Screening and Molecular Dynamics Simulation studies can suggest good leads for drug designing. The novelty of this study is that the workflow used here yields the same results that are at par with the experimental data.

Conclusion: This suggests the use of the 2D fingerprint similarity search in various databases, followed by multiple docking algorithms and dynamics as a workflow that will lead to finding novel compounds that a structurally and functionally similar to LEF and BREQ.

简介：类风湿关节炎（RA）是一种自身免疫性疾病，可引起关节的慢性炎症。人二氢Orotate脱氢酶[DHODH]是治疗类风湿关节炎的临床有效药物靶标。DHODH抑制产生有益的免疫抑制剂和抗增殖作用。

材料与方法：用于治疗RA的药物来氟米特[LEF]和布雷喹钠[BREQ]抑制引起炎症的免疫细胞，但有数种副作用，其中主要是症状性肝损害和毒性。现有的基于LEF和BREQ结构相似性的支架用于在ZINC数据库中使用2D二进制指纹筛选出有效的DHODH抑制剂。由于其Tanimoto相似系数，将10个与支架相似的结构入围。使用工具AutoDock，Ligand fit和iGEMDOCK将选定的结构与目标人类DHODH对接。检查了具有与支架相似的相互作用的高得分化合物，以评估其药物敏感性。

结果：然后使用GROMACS对入围的5种化合物进行了50ns的分子动力学模拟研究。基于二维指纹筛选和分子动力学模拟研究的结构相似性度量可以为药物设计提供良好的线索。这项研究的新颖之处在于，此处使用的工作流程所产生的结果与实验数据相同。

结论：这表明在各种数据库中使用2D指纹相似性搜索，然后使用多个对接算法和动力学作为工作流，这将导致发现结构和功能上与LEF和BREQ相似的新型化合物。