An in silico Workflow that Yields Experimentally Comparable Inhibitors for Human Dihydroorotate Dehydrogenase
| Autor: | B Poorani, Priya Swaminathan, M Sucharita |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Oxidoreductases Acting on CH-CH Group Donors
Structural similarity In silico Dihydroorotate Dehydrogenase Computational biology Molecular Dynamics Simulation 01 natural sciences Workflow 03 medical and health sciences Drug Discovery medicine Humans Computer Simulation Enzyme Inhibitors 030304 developmental biology Leflunomide Brequinar sodium 0303 health sciences Chemistry Biphenyl Compounds General Medicine AutoDock medicine.disease 0104 chemical sciences 010404 medicinal & biomolecular chemistry Docking (molecular) Rheumatoid arthritis Drug Design Dihydroorotate dehydrogenase Molecular Medicine medicine.drug |
| Zdroj: | Current computer-aided drug design. 16(3) |
| ISSN: | 1875-6697 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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