An in silico Workflow that Yields Experimentally Comparable Inhibitors for Human Dihydroorotate Dehydrogenase

Author(s): Sucharita M., Poorani B., Priya Swaminathan*

Journal Name: Current Computer-Aided Drug Design

Volume 16 , Issue 3 , 2020

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Graphical Abstract:


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.

Keywords: DHODH, scaffold, 2D binary fingerprints, molecular dynamics simulation leflunomide, brequinar sodium, dehydrogenase.

Firestein, G.S. Evolving concepts of rheumatoid arthritis. Nature, 2003, 423(6937), 356-361.
[] [PMID: 12748655]
Firestein, G.S. Pathogenesis of rheumatoid arthritis: how early is early? Arthritis Res. Ther., 2005, 7(4), 157-159.
[] [PMID: 15987499]
Kahlenberg, J.M.; Fox, D.A. Advances in the medical treatment of rheumatoid arthritis. Hand Clin., 2011, 27(1), 11-20.
[] [PMID: 21176795]
Breedveld, F.C.; Dayer, J.M. Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann. Rheum. Dis., 2000, 59(11), 841-849.
[] [PMID: 11053058]
Davis, J.P.; Cain, G.A.; Pitts, W.J.; Magolda, R.L.; Copeland, R.A. The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase. Biochemistry, 1996, 35(4), 1270-1273.
[] [PMID: 8573583]
Aithal, G.P. Hepatotoxicity related to antirheumatic drugs. Nat. Rev. Rheumatol., 2011, 7(3), 139-150.
[] [PMID: 21263458]
Chen, S.F.; Perrella, F.W.; Behrens, D.L.; Papp, L.M. Inhibition of dihydroorotate dehydrogenase activity by brequinar sodium. Cancer Res., 1992, 52(13), 3521-3527.
[PMID: 1617622]
Maroun, J.; Ruckdeschel, J.; Natale, R.; Morgan, R.; Dallaire, B.; Sisk, R.; Gyves, J. Multicenter phase II study of brequinar sodium in patients with advanced lung cancer. Cancer Chemother. Pharmacol., 1993, 32(1), 64-66.
[] [PMID: 8384937]
Vyas, V.K.; Ghate, M. QSAR study on a series of aryl carboxylic acid amide derivatives as potential inhibitors of dihydroorotate dehydrogenase (DHODH). Med. Chem., 2013, 9(2), 222-239.
[] [PMID: 22920152]
Abdullah, I.; Chee, C.F.; Lee, Y.K.; Thunuguntla, S.S.; Satish Reddy, K.; Nellore, K.; Antony, T.; Verma, J.; Mun, K.W.; Othman, S.; Subramanya, H.; Rahman, N.A. Benzimidazole derivatives as potential dual inhibitors for PARP-1 and DHODH. Bioorg. Med. Chem., 2015, 23(15), 4669-4680.
[] [PMID: 26088338]
Munier-Lehmann, H.; Lucas-Hourani, M.; Guillou, S.; Helynck, O.; Zanghi, G.; Noel, A.; Tangy, F.; Vidalain, P.O.; Janin, Y.L. Original 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as inhibitors of human dihydroorotate dehydrogenase (DHODH). J. Med. Chem., 2015, 58(2), 860-877.
[] [PMID: 25558988]
Erra, M.; Moreno, I.; Sanahuja, J.; Andrés, M.; Reinoso, R.F.; Lozoya, E.; Pizcueta, P.; Godessart, N.; Castro-Palomino, J.C. Biaryl analogues of teriflunomide as potent DHODH inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(24), 7268-7272.
[] [PMID: 22078215]
Lolli, M.L.; Giorgis, M.; Tosco, P.; Foti, A.; Fruttero, R.; Gasco, A. New inhibitors of dihydroorotate dehydrogenase (DHODH) based on the 4-hydroxy-1,2,5-oxadiazol-3-yl (hydroxyfurazanyl) scaffold. Eur. J. Med. Chem., 2012, 49, 102-109.
[] [PMID: 22245049]
Willett, P. Similarity searching using 2D structural fingerprints. Methods Mol. Biol., 2011, 672, 133-158.
[] [PMID: 20838967]
Barnard, J.; Downs, G. Clustering of chemical structures on the basis of two-dimensional similarity measures. J. Chem. Inf. Model., 1992, 32(6), 644-649.
Böckmann, R.A.; Grubmüller, H. Nanoseconds molecular dynamics simulation of primary mechanical energy transfer steps in F1-ATP synthase. Nat. Struct. Biol., 2002, 9(3), 198-202.
[] [PMID: 11836535]
Backman, T.W.; Cao, Y.; Girke, T. ChemMine tools: an online service for analyzing and clustering small molecules. Nucleic Acids Res., 2011, 39(Web Server issue)(Suppl.)W486-91,
[] [PMID: 21576229]
Willett, P. Similarity-based virtual screening using 2D fingerprints. Drug Discov. Today, 2006, 11(23-24), 1046-1053.
[] [PMID: 17129822]
Godden, J.W.; Xue, L.; Bajorath, J. Combinatorial preferences affect molecular similarity/diversity calculations using binary fingerprints and Tanimoto coefficients. J. Chem. Inf. Comput. Sci., 2000, 40(1), 163-166.
[] [PMID: 10661563]
Holliday, J.D.; Salim, N.; Whittle, M.; Willett, P. Analysis and display of the size dependence of chemical similarity coefficients. J. Chem. Inf. Comput. Sci., 2003, 43(3), 819-828.
[] [PMID: 12767139]
Girke, T.; Cheng, L.C.; Raikhel, N. ChemMine. A compound mining database for chemical genomics. Plant Physiol., 2005, 138(2), 573-577.
[] [PMID: 15955920]
Pronk, S.; Páll, S.; Schulz, R.; Larsson, P.; Bjelkmar, P.; Apostolov, R.; Shirts, M.R.; Smith, J.C.; Kasson, P.M.; van der Spoel, D.; Hess, B.; Lindahl, E. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics, 2013, 29(7), 845-854.
[] [PMID: 23407358]
Berendsen, H.; van der Spoel, D.; van Drunen, R. GROMACS: A message-passing parallel molecular dynamics implementation. Comput. Phys. Commun., 1995, 91(1-3), 43-56.
Schuler, L.; Daura, X.; van Gunsteren, W. An improved GROMOS96 force field for aliphatic hydrocarbons in the condensed phase. J. Comput. Chem., 2001, 22(11), 1205-1218.
Venkatachalam, C.M.; Jiang, X.; Oldfield, T.; Waldman, M. LigandFit: a novel method for the shape-directed rapid docking of ligands to protein active sites. J. Mol. Graph. Model., 2003, 21(4), 289-307.
[] [PMID: 12479928]
Goodsell, D.S.; Morris, G.M.; Olson, A.J. Automated docking of flexible ligands: applications of AutoDock. J. Mol. Recognit., 1996, 9(1), 1-5.
[<1:AID-JMR241>3.0.CO;2-6] [PMID: 8723313]
Hsu, K.C.; Chen, Y.F.; Lin, S.R.; Yang, J.M. iGEMDOCK: a graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis. BMC Bioinformatics, 2011, 12(Suppl. 1), S33.
[] [PMID: 21342564]
Warren, G.L.; Andrews, C.W.; Capelli, A.M.; Clarke, B.; LaLonde, J.; Lambert, M.H.; Lindvall, M.; Nevins, N.; Semus, S.F.; Senger, S.; Tedesco, G.; Wall, I.D.; Woolven, J.M.; Peishoff, C.E.; Head, M.S. A critical assessment of docking programs and scoring functions. J. Med. Chem., 2006, 49(20), 5912-5931.
[] [PMID: 17004707]
Cheng, F.; Li, W.; Zhou, Y.; Shen, J.; Wu, Z.; Liu, G.; Lee, P.W.; Tang, Y. admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. J. Chem. Inf. Model., 2012, 52(11), 3099-3105.
[] [PMID: 23092397]
Hess, B.; Kutzner, C.; van der Spoel, D.; Lindahl, E. GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. J. Chem. Theory Comput., 2008, 4(3), 435-447.
[] [PMID: 26620784]
Spessard, G. ACD Labs/LogP dB 3.5 and ChemSketch 3.5. J. Chem. Inf. Comput. Sci., 1998, 38(6), 1250-1253.
Small, Y.A.; Guallar, V.; Soudackov, A.V.; Hammes-Schiffer, S. Hydrogen bonding pathways in human dihydroorotate dehydrogenase. J. Phys. Chem. B, 2006, 110(39), 19704-19710.
[] [PMID: 17004840]
Mongan, J. Interactive essential dynamics. J. Comput. Aided Mol. Des., 2004, 18(6), 433-436.
[] [PMID: 15663003]
Matter, H.; Pötter, T. Comparing 3D Pharmacophore Triplets and 2D Fingerprints for Selecting Diverse Compound Subsets. J. Chem. Inf. Comput. Sci., 1999, 39, 1211-1225.

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Article Details

Year: 2020
Published on: 02 June, 2020
Page: [340 - 350]
Pages: 11
DOI: 10.2174/1573409915666190528114703
Price: $65

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