| Discovery of Novel Nonpolar Interactions Between Influenza Neuraminidase and Oseltamivir and Its Implication on Virtual Screening |
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Presentation: 1C02 Session: Library Design and Virtual HTSXiaowu Chen, James M. Chen, and S. Swaminathan, Gilead Sciences Presenting Author: Xiaowu Chen, Gilead Sciences - USA During the discovery of the first oral drug that targets influenza neuraminidase (NA), we discovered a novel nonpolar interaction between an NA binding pocket and a potent inhibitor GS4071 (Oseltamivir). This apparently highly polar pocket interacts favorably with the hydrophobic alkyl moiety of GS4071, this unusual interaction plays an essential role in determining the potency of GS4071. We hypothesize that the pi-faces of the sp2 planar termini of these polar pocket residues may behave similarly to those of aromatic rings and therefore could interact favorably with hydrophobic moieties of a bound inhibitor. Given the progress made in virtual screening technologies since then, a retrospective study was conducted utilizing these newer methods. The objective here is to determine whether virtual screening would have added value towards the discovery of GS4071. In addition, we want to find out whether or not today's scoring functions can sufficiently take this novel interaction into consideration. |