Structure Based Design And Synthesis Of Potential Dengue Virus NS2B-NS3 Protease Inhibitors
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Date
2018-04
Authors
Sinha, Suman
Journal Title
Journal ISSN
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Publisher
Universiti Sains Malaysia
Abstract
Dengue is transmitted by the bite of a mosquito infected with one of the five dengue virus serotypes. As far as anti-dengue drug discovery is concerned, among few established therapeutic targets, NS2B-NS3 protease is quite popular due to its role in production of mature viruses and plays a key role in maintaining infectivity. The work in this thesis described the computational and experimental studies in the design and synthesis of novel NS2B-NS3 protease from natural scaffolds such as lawsone and ferulic acid. In the case of naphthoquinone class of compounds, it was understood from docking studies that incorporation of molecular flexibility could lead to tighter binding compounds. Simultaneously, rational scaffold minimizing approach was undertaken with an aim to reduce molecule size to develop low molecular weight compounds also proved fruitful in the design pathway from anthraquinone to naphthoquinone. Detailed molecular docking and interaction analysis led to the prediction that compounds vanillin (VAN) and lawsone (LAW) could be experimentally active. Subsequent enzymatic assay of these two compounds against NS2B-NS3 protease proved that vanillin and lawsone were active with IC50 of 108 μM and 878 μM, respectively. Further design based on molecular docking studies led to the synthesis of derivatives of lawsone and vanillin. The selected compounds belonged to three distinct chemical classes, binaphthoquinones, aminonaphthoquinones and α-(arylamino) cinnamic acids. All the synthesized compounds were characterized by FTIR, proton and 13C NMR, as well as mass spectroscopy. Finally, enzymatic inhibition studies led to the identification compound SS-2 (binaphthoquinone scaffold) and SS-5 (amino naphthoquinone) which showed IC50 of 37.92 μM and 0.0065 μM respectively. Overall, the structure based design approach and subsequent experimental validation through the present work successfully proved the concept of computer aided drug design.
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Keywords
Structure based design and synthesis , of potential dengue virus