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netLibrary - eBook Summary Structure-based Drug Design by ...

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Document<br />

Figure 10<br />

Possible hydrogen bonds in the pore region of HRV14 bound to WIN<br />

61605 (ball and stick). The waters (spheres W1 and W2) could<br />

potentially form hydrogen bonds to WIN 61605 as well as the side<br />

chains of Asn1219 and Ser1107 as well as the backbone of Leu1106<br />

(residues highlighted as tubes). The viewer is looking<br />

from the virion exterior.<br />

Page 512<br />

The fluidity of the hydrogen-bond donation network at the pore could allow a large number of<br />

structurally distinct molecules to bind in this location. If the function of the pocket is to bind fatty acids<br />

or other structurally diverse pocket factors and thus stabilize the virion. The flexibility of the hydrogenbonding<br />

network at the pore seems ideally suited for such a purpose.<br />

<strong>Drug</strong> Flexibility<br />

The WIN compounds all contain a flexible linking region that allows them to conform to differently<br />

shaped interiors of VP1 hydrophobic pockets. This flexibility is seen in many compounds that share the<br />

WIN-drug mechanism of action. However, some compounds do not contain a region as obviously<br />

flexible as an aliphatic linker (e.g., those with unsaturated rings as linkers, Figure 5).<br />

Flexibility in the aliphatic linking region of the WIN compounds has been explicitly studied and the<br />

results suggest that such a property is important for<br />

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