Potential Neuraminidase Inhibitors Via Virtual Screening, Kinetic Studies, And Adme Predictions
| dc.contributor.author | Nuwarda, Rina Fajri | |
| dc.date.accessioned | 2017-02-10T00:40:28Z | |
| dc.date.available | 2017-02-10T00:40:28Z | |
| dc.date.issued | 2015-10 | |
| dc.description.abstract | Neuraminidase (NA) activity plays an important role in the infection by influenza viruses by facilitating the release of the newly formed virions from the host cell receptor and promotes its infection to other cells or organs. With the emergence of viral resistance towards the existing NA inhibitors, the discovery of new NA inhibitors is urgently needed. In this work, docking-based virtual screening of large compounds from NCI database to rapidly select in silico hits to be potential NA inhibitors was carried out. A new in vitro method has been attempted to be developed for NA inhibition assay by utilizing AlphaScreenTM technology with Alpha-1-Acid glycoprotein as a substrate. Unfortunately, this effort was unsuccessful probably due to the non-specific cleavage of sialic acid by NA. Subsequently, a traditional MUNANA assay was performed to investigate the inhibitory activities and kinetic parameters of the inhibitor compounds. Finally, the selected compounds were studied for their pharmacokinetic properties in silico. From the NCI database, 1541 compounds have been successfully screened and 40 in silico hits compounds were obtained, and assayed to determine their IC50s. Ten of them demonstrated over 50% inhibition against NA and four compounds namely NSC 5069, NSC 83318, NSC 156563, and NSC 134137 were found having IC50 values of 216 μM, 320 μM, 571 μM and 673 μM, respectively. The kinetic studies showed Km value for MUNANA was 36.44 μM and Vmax for the enzymatic reaction was 551.25 RFU/min. From the Dixon plot, these four compounds appeared to competitively inhibit the neuraminidase with Ki values for NSC 5069, NSC 83318, NSC 156563, and NSC 134137 were 100.26, 204.13, 202.90, and 197.75 μM, respectively. Drug-likeness properties assessment predicting the physicochemical properties such as molecular weight, Log P, number of hydrogen bond donor and acceptor fulfilled Lipinski's Rule of Five. The results of pKa value showed that the compounds are weakly acidic and tend to be absorbed in the intestine (NSC 5069 with pKa value 4.1, NSC 83318 with pKa value 6.3 and), and stonger acidic compound to be absorbed in the gastrik (NSC 156563 and NSC 134137 with pKa value 2.7). In silico calculations of TPSA showed that NSC 83318 and NSC 156563 fulfill Lipinski's criteria of having TPSA value less than 140 Å2, while NSC 5069 and NSC 134137 were predicted to have poor permeation since their TPSA values are more than the acceptable upper limit of 140 Å2. Based on the fraction’s absorbed percentage, NSC 5069 and NSC 83318 were considered to have high fraction for the absorption. While the other two compounds, NSC 156563 and NSC 134137 had low fraction for the absorption. In predicting volume distribution, the results showed that the volume distribution of NSC 5069, NSC 83318, NSC 156563, NSC 134137 were 0.86 L/kg, 0.7 L/kg, 0.13 L/kg and 0.12 L/kg, respectively. NSC 83318, NSC 156563, and NSC 134137 have %PPB more than 90% which means that almost all the compounds administered may be bound to the plasma protein in the body, whereas NSC 5069 has %PPB 57%, indicating that 57% of the compound is bound to the plasma proteins. Lastly, the four top compounds showed no probability as substrates or inhibitors for almost all CYP isoforms, except for NSC 83318 which showed relatively high probability to act on CYP 1A2 with value 0.84. | en_US |
| dc.identifier.uri | http://hdl.handle.net/123456789/3697 | |
| dc.language.iso | en | en_US |
| dc.publisher | Universiti Sains Malaysia | en_US |
| dc.subject | Neuraminidase | en_US |
| dc.title | Potential Neuraminidase Inhibitors Via Virtual Screening, Kinetic Studies, And Adme Predictions | en_US |
| dc.type | Thesis | en_US |
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