tetano
Editor, Senior Moderator
J Chem Inf Model. 2015 Dec 24. [Epub ahead of print]
[h=1]H274Y's Effect on Oseltamivir Resistance: What Happens Before the Drug Enters the Binding Site.[/h] Yusuf M, Mohamed N, Mohamad S, Janezic D, Damodaran KV, Wahab H.
[h=3]Abstract[/h] Increased reports of oseltamivir (OTV) resistant strains of the influenza virus, such as H274Y mutation on its neuraminidase (NA), have created some cause for concern. Many studies were conducted in the attempt to uncover the mechanism of OTV resistance in H274Y NA. However, most of the reported studies on H274Y only focused on the drug-bound system, but direct effects of the mutation toward NA itself prior to drug binding still remain unclear. Therefore, molecular dynamics simulations of NA in apo form, followed by principal component analysis and interaction energy calculation, were performed to investigate the structural changes of the NA binding site as a result of H274Y mutation. It was observed that the disruption of the NA binding site due to H274Y was initiated by the repulsive effect of Y274 on the 250-loop, which in turn altered the hydrogen bond network around residue 274. The rotated W295 side chain caused the upward movement of the 340-loop. Consequently, sliding box docking results suggested that the binding pathway of OTV was compromised due to the disruption of this binding site. This study also highlighted the importance of the functional group at position C6 of sialic acid mimicry. It is hoped that these results could improve the understanding of OTV resistances and shed some light on the design of a novel anti-influenza drug.
PMID: 26703840 [PubMed - as supplied by publisher]
[h=1]H274Y's Effect on Oseltamivir Resistance: What Happens Before the Drug Enters the Binding Site.[/h] Yusuf M, Mohamed N, Mohamad S, Janezic D, Damodaran KV, Wahab H.
[h=3]Abstract[/h] Increased reports of oseltamivir (OTV) resistant strains of the influenza virus, such as H274Y mutation on its neuraminidase (NA), have created some cause for concern. Many studies were conducted in the attempt to uncover the mechanism of OTV resistance in H274Y NA. However, most of the reported studies on H274Y only focused on the drug-bound system, but direct effects of the mutation toward NA itself prior to drug binding still remain unclear. Therefore, molecular dynamics simulations of NA in apo form, followed by principal component analysis and interaction energy calculation, were performed to investigate the structural changes of the NA binding site as a result of H274Y mutation. It was observed that the disruption of the NA binding site due to H274Y was initiated by the repulsive effect of Y274 on the 250-loop, which in turn altered the hydrogen bond network around residue 274. The rotated W295 side chain caused the upward movement of the 340-loop. Consequently, sliding box docking results suggested that the binding pathway of OTV was compromised due to the disruption of this binding site. This study also highlighted the importance of the functional group at position C6 of sialic acid mimicry. It is hoped that these results could improve the understanding of OTV resistances and shed some light on the design of a novel anti-influenza drug.
PMID: 26703840 [PubMed - as supplied by publisher]