Combinatorial design of virtual sialic acid analogues against influenza a hemagglutinin using structure and fragment based approaches
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Date
2009
Authors
Mahmoud Al-qattan, Mohammed Noor Al-deen
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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.
Description
Master
Keywords
Chemical science , Sialic acid , Influenza a hemagglutinin