| Autor: |
Prachanronarong KL, Özen A, Thayer KM, Yilmaz LS, Zeldovich KB, Bolon DN, Kowalik TF, Jensen JD; School of Life Sciences, École Polytechnique Fédérale de Lausanne , 1015 Lausanne, Switzerland., Finberg RW, Wang JP, Kurt-Yilmaz N, Schiffer CA |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of chemical theory and computation [J Chem Theory Comput] 2016 Dec 13; Vol. 12 (12), pp. 6098-6108. Date of Electronic Publication: 2016 Nov 17. |
| DOI: |
10.1021/acs.jctc.6b00703 |
| Abstrakt: |
Neuraminidase (NA) inhibitors are used for the prevention and treatment of influenza A virus infections. Two subtypes of NA, N1 and N2, predominate in viruses that infect humans, but differential patterns of drug resistance have emerged in each subtype despite highly homologous active sites. To understand the molecular basis for the selection of these drug resistance mutations, structural and dynamic analyses on complexes of N1 and N2 NA with substrates and inhibitors were performed. Comparison of dynamic substrate and inhibitor envelopes and interactions at the active site revealed how differential patterns of drug resistance have emerged for specific drug resistance mutations, at residues I222, S246, and H274 in N1 and E119 in N2. Our results show that the differences in intermolecular interactions, especially van der Waals contacts, of the inhibitors versus substrates at the NA active site effectively explain the selection of resistance mutations in the two subtypes. Avoiding such contacts that render inhibitors vulnerable to resistance by better mimicking the dynamics and intermolecular interactions of substrates can lead to the development of novel inhibitors that avoid drug resistance in both subtypes. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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