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Ensemble-based virtual screening reveals potential novel antiviral compounds for avian influenza neuraminidase.

ABSTRACT: Avian influenza virus subtype H5N1 is a potential pandemic threat with human-adapted strains resistant to antiviral drugs. Although virtual screening (VS) against a crystal or relaxed receptor structure is an established method to identify potential inhibitors, the more dynamic changes within binding sites are neglected. To accommodate full receptor flexibility, we use AutoDock4 to screen the NCI diversity set against representative receptor ensembles extracted from explicitly solvated molecular dynamics simulations of the neuraminidase system. The top hits are redocked to the entire nonredundant receptor ensemble and rescored using the relaxed complex scheme (RCS). Of the 27 top hits reported, half ranked very poorly if only crystal structures are used. These compounds target the catalytic cavity as well as the newly identified 150- and 430-cavities, which exhibit dynamic properties in electrostatic surface and geometric shape. This ensemble-based VS and RCS approach may offer improvement over existing strategies for structure-based drug discovery.

SUBMITTER: Cheng LS

PROVIDER: S-EPMC2652358 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Ensemble-based virtual screening reveals potential novel antiviral compounds for avian influenza neuraminidase.

Cheng Lily S LS Amaro Rommie E RE Xu Dong D Li Wilfred W WW Arzberger Peter W PW McCammon J Andrew JA

Journal of medicinal chemistry 20080618 13

Avian influenza virus subtype H5N1 is a potential pandemic threat with human-adapted strains resistant to antiviral drugs. Although virtual screening (VS) against a crystal or relaxed receptor structure is an established method to identify potential inhibitors, the more dynamic changes within binding sites are neglected. To accommodate full receptor flexibility, we use AutoDock4 to screen the NCI diversity set against representative receptor ensembles extracted from explicitly solvated molecular ...[more]

PMID: 18558668

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Project description:Several subtypes of avian influenza viruses (AIVs) are emerging as novel human pathogens, and the frequency of related infections has increased in recent years. Although neuraminidase (NA) inhibitors (NAIs) are the only class of antiviral drugs available for therapeutic intervention for AIV-infected patients, studies on NAI resistance among AIVs have been limited, and markers of resistance are poorly understood. Previously, we identified unique NAI resistance substitutions in AIVs of the N3, N7, and N9 NA subtypes. Here, we report profiles of NA substitutions that confer NAI resistance in AIVs of the N4, N5, N6, and N8 NA subtypes using gene-fragmented random mutagenesis. We generated libraries of mutant influenza viruses using reverse genetics (RG) and selected resistant variants in the presence of the NAIs oseltamivir carboxylate and zanamivir in MDCK cells. In addition, two substitutions, H274Y and R292K (N2 numbering), were introduced into each NA gene for comparison. We identified 37 amino acid substitutions within the NA gene, 16 of which (4 in N4, 4 in N5, 4 in N6, and 4 in N8) conferred resistance to NAIs (oseltamivir carboxylate, zanamivir, or peramivir) as determined using a fluorescence-based NA inhibition assay. Substitutions conferring NAI resistance were mainly categorized as either novel NA subtype specific (G/N147V/I, A246V, and I427L) or previously reported in other subtypes (E119A/D/V, Q136K, E276D, R292K, and R371K). Our results demonstrate that each NA subtype possesses unique NAI resistance markers, and knowledge of these substitutions in AIVs is important in facilitating antiviral susceptibility monitoring of NAI resistance in AIVs.IMPORTANCE The frequency of human infections with avian influenza viruses (AIVs) has increased in recent years. Despite the availability of vaccines, neuraminidase inhibitors (NAIs), as the only available class of drugs for AIVs in humans, have been constantly used for treatment, leading to the inevitable emergence of drug-resistant variants. To screen for substitutions conferring NAI resistance in AIVs of N4, N5, N6, and N8 NA subtypes, random mutations within the target gene were generated, and resistant viruses were selected from mutant libraries in the presence of individual drugs. We identified 16 NA substitutions conferring NAI resistance in the tested AIV subtypes; some are novel and subtype specific, and others have been previously reported in other subtypes. Our findings will contribute to an increased and more comprehensive understanding of the mechanisms of NAI-induced inhibition of influenza virus and help lead to the development of drugs that bind to alternative interaction motifs.

Dataset Information

Ensemble-based virtual screening reveals potential novel antiviral compounds for avian influenza neuraminidase.

Publications

Ensemble-based virtual screening reveals potential novel antiviral compounds for avian influenza neuraminidase.

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