Combinatorial design of virtual sialic acid analogues against influenza a hemagglutinin using structure and fragment based approaches
| dc.contributor.author | Mahmoud Al-qattan, Mohammed Noor Al-deen | |
| dc.date.accessioned | 2014-11-03T02:11:08Z | |
| dc.date.available | 2014-11-03T02:11:08Z | |
| dc.date.issued | 2009 | |
| dc.description | Master | en_US |
| dc.description.abstract | Inhibition of influenza A virus to avoid morbidity and mortality is of main concern during epidemics and of major concern during pandemics. Two types of surface glycoprotein form the main surface antigenic determinants of influenza A virus i.e. hemagglutinin (HA) and neuraminidase (NA). HA is responsible for viral attachment to the infected cell through surface-bound sialic acid (SA) moieties, while NA is responsible for hydrolysing the glycosidic bond that connects SA with the cell membrane resulting in viral detachment. Structure-based drug design approach has been successfully used in designing the clinically available NA inhibitors Zenamivir and Oseltamivir which restrict the progeny virus detachment. However, there is no effective low molecular weight inhibitor that has been developed to target HA and prevent the initial viral attachment to the host cell. In this study molecular modeling techniques were used to design databases of virtual SA analogues by a single substitution at either of C2, C5 or C6 positions of SA scaffold. A commercially available molecular fragment was used for the substitution candidate. By using molecular docking approach, the molecular fragments were docked against the HA binding pocket at the crystallographic binding sites of C2-, C5- and C6-natural functional groups of SA and its analogues. Then, the oriented fragments were connected automatically to the SA scaffold with or without the incorporation of molecular linkers using in-house developed empirical algorithms. Thus, three databases of SA analogues with single substituted fragments at positions C2, C5 or C6 were successfully generated. The three databases were then docked against the whole SA binding site using a validated docking tool to estimate the accurate binding conformations and affinities. Our docking results showed that the affinities of the generated analogues were higher (up to 30,000 fold) than the natural SA. The improvement in binding energies indicates that the favourable binding energies of the oriented fragments and the crystal SA scaffolds were additively merged within the generated analogues. Using the C5-derived and C6-derived SA analogues that showed higher affinities with little deviations from the crystal SA scaffold’s position, a database of combinatorial SA analogues was generated by extracting the C5- and C6-designed substitutions and combining them systematically on a single SA scaffold molecule. The Lipinski’s rule of five was applied to construct only the oral bioavailable analogues. The docking results showed that the affinities of combinatorial analogues were higher than the analogues of single substitution and exceed 100,000 fold the affinity of natural SA. As many of the designed SA analogues could bind the SA binding site of HA with higher affinity than the natural SA, they have the potential to inhibit influenza A virus from attachment to host cell membrane and consequently act as anti-flu agents. | en_US |
| dc.identifier.uri | http://hdl.handle.net/123456789/220 | |
| dc.language.iso | en | en_US |
| dc.subject | Chemical science | en_US |
| dc.subject | Sialic acid | en_US |
| dc.subject | Influenza a hemagglutinin | en_US |
| dc.title | Combinatorial design of virtual sialic acid analogues against influenza a hemagglutinin using structure and fragment based approaches | en_US |
| dc.type | Thesis | en_US |
Files
License bundle
1 - 1 of 1
Loading...
- Name:
- license.txt
- Size:
- 1.71 KB
- Format:
- Item-specific license agreed upon to submission
- Description: