Title

Molecular Basis for Differential Patterns of Drug Resistance in Influenza N1 and N2 Neuraminidase

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Program in Bioinformatics and Integrative Biology; Program in Systems Biology; Department of Microbiology and Physiological Systems; Department of Medicine

Publication Date

2016-12-13

Document Type

Article

Disciplines

Biochemistry | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Molecular Biology | Structural Biology | Virus Diseases

Abstract

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.

DOI of Published Version

10.1021/acs.jctc.6b00703

Source

J Chem Theory Comput. 2016 Dec 13;12(12):6098-6108. Epub 2016 Nov 17. Link to article on publisher's site

Journal/Book/Conference Title

Journal of chemical theory and computation

Related Resources

Link to Article in PubMed

PubMed ID

27951676

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