H274Y’s Effect on Oseltamivir Resistance: What Happens Before the Drug Enters the Binding Site

• DOI: 10.1021/acs.jcim.5b00331
• Publication Date: 2015-12-24T18:09:23Z
• Authors: Muhammad Yusuf; Nornisah Mohamed; Suriyati Mohamad; Dusanka Janezic; K. V. Damodaran; Habibah A. Wahab
• Keywords: Oseltamivir; Neuraminidase inhibitor; Docking (animal)

Increased reports of oseltamivir (OTV)-resistant strains the influenza virus, such as H274Y mutation on its neuraminidase (NA), have created some cause for concern. Many studies been conducted in attempt to uncover mechanism OTV resistance NA. However, most reported focused only drug-bound system, so direct effects NA itself prior drug binding still remain unclear. Therefore, molecular dynamics simulations apo form, followed by principal component analysis and interaction energy calculations, were performed investigate structural changes site a result mutation. It was observed that disruption due initiated repulsive effect Y274 250-loop, which turn altered hydrogen-bonding network around residue 274. The rotated W295 side chain caused upward movement 340-loop. Consequently, sliding box docking results suggested pathway compromised because this site. This study also highlighted importance functional group at C6 sialic acid mimicry. is hoped these will improve understanding shed light design novel anti-influenza drug.