Keywords
Antiviral
Autodock 1.5.6
NS5 Protein
How to Cite
Abstract
In an attempt to find potential antiviral agents, a series of pyrazolones (PA1-PA6& PC1-PC6) were designed and evaluated for their  DENVNS5 (RNA-dependent RNA polymerase) inhibitory activity. Molecular docking studies of all the designed compounds into the binding site of DENVNS5 (PDB Code: 4C11) were performed to gain a comprehensive understanding into rational binding modes. These compounds were also screened for in silico drug-likeliness properties on the basis of the absorption, distribution, metabolism and excretion (ADME) prediction. Among all the synthesized compounds, analogue  PA6showed superior inhibitory activity against RNA dependent RNA polymerase. SAR  study indicated that the presence of an electron withdrawing substitution on pyrazolone derivatives significantly improves its binding interaction with the protein.Results of ADME prediction revealed that most of these compounds showed in silico drug-likeliness.References
Mariappan, G.; Saha, B. P.; Sutharson, L.; Ankits, G.; Pandey, L.; Kumar, D. The diverse pharmacological importance of pyrazolone derivatives: A Review. J Pharm Res 2010, 3, 2856-2859.
Fischer, E.; Knoevenagel, O. 2) Ueber die Verbindungen des Phenylhydrazins mit Acroleïn, Mesityloxyd und Allylbromid). Justus Liebigs Ann Chem 1887, 239 (2), 194-206.
https://doi.org/10.1002/jlac.18872390205
Gupta, P.; Gupta, J. K.; Halve, A. K. Synthesis and Biological Significance of Pyrazolones: A Review. Int J Pharm Sci 2015, 6 (6), 2291-2310.
Knorr, L. Einwirkung von Acetessigester auf Phenylhydrazin. Ber Dtsch Chem Ges 1883, 16 (2), 2597-2599.
https://doi.org/10.1002/cber.188301602194
Knorr, L. Synthetische Versuche mit dem Acetessigester. Justus Liebigs Ann Chem 1887, 238 (1â€2), 137-219.
https://doi.org/10.1002/jlac.18872380107
Hughes, J. P.; Rees, S.; Kalindjian, S. B.; Philpott, K. L. Principles of early drug discovery. Br J Pharmacol 2011, 162 (6), 1239-1249.
https://doi.org/10.1111/j.1476-5381.2010.01127.x
Baldi, A. Computational approaches for drug design and discovery: An overview. Sys Rev Pharm 2010, 1 (1), 99.
https://doi.org/10.4103/0975-8453.59519
Behnam, M. A. M.; Nitsche, C.; Boldescu, V.; Klein, C. D. The medicinal chemistry of dengue virus. J Med Chem 2016, 59 (12), 5622-5649.
https://doi.org/10.1021/acs.jmedchem.5b01653
Stevens, A. J.; Gahan, M. E.; Mahalingam, S.; Keller, P. A. The medicinal chemistry of dengue fever. J Med Chem 2009, 52 (24), 7911-7926.
https://doi.org/10.1021/jm900652e
Nitsche, C.; Holloway, S.; Schirmeister, T.; Klein, C. D. Biochemistry and medicinal chemistry of the dengue virus protease. Chem Rev 2014, 114 (22), 11348-11381.
https://doi.org/10.1021/cr500233q
Johansson, M.; Brooks, A. J.; Jans, D. A.; Vasudevan, S. G. A small region of the dengue virus-encoded RNA-dependent RNA polymerase, NS5, confers interaction with both the nuclear transport receptor importin-β and the viral helicase, NS3. J Gen Virol 2001, 82 (4), 735-745.
https://doi.org/10.1099/0022-1317-82-4-735
Selisko, B.; Peyrane, F. F.; Canard, B.; Alvarez, K.; Decroly, E. Biochemical characterization of the (nucleoside-2′ O)-methyltransferase activity of dengue virus protein NS5 using purified capped RNA oligonucleotides 7MeGpppACn and GpppACn. J Gen Virol 2010, 91 (1), 112-121.
https://doi.org/10.1099/vir.0.015511-0
Tan, B.-H.; Fu, J.; Sugrue, R. J.; Yap, E.-H.; Chan, Y.-C.; Tan, Y. H. Recombinant Dengue Type 1 Virus NS5 Protein Expressed inEscherichia coliExhibits RNA-Dependent RNA Polymerase Activity. Virology 1996, 216 (2), 317-325.
https://doi.org/10.1006/viro.1996.0067
Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R. K.; Goodsell, D. S.; Olson, A. J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009, 30 (16), 2785-2791.
https://doi.org/10.1002/jcc.21256
Lim, S. P.; Koh, J. H. K.; Seh, C. C.; Liew, C. W.; Davidson, A. D.; Chua, L. S.; Chandrasekaran, R.; Cornvik, T. C.; Shi, P.-Y.; Lescar, J. A Crystal Structure of the Dengue Virus Non-structural Protein 5 (NS5) Polymerase Delineates Interdomain Amino Acid Residues That Enhance Its Thermostability and de Novo Initiation Activities. J Biol Chem 2013, 288 (43), 31105-31114.
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.