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    Binding modes of diketo-acid inhibitors of HIV-1 integrase: a comparative molecular dynamics simulation study.

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    Authors
    Huang, Meilan
    Grant, Guy H.
    Richards, W. Graham
    Affiliation
    Queens University Belfast
    Issue Date
    2011-06
    
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    Abstract
    HIV-1 integrase (IN) has become an attractive target since drug resistance against HIV-1 reverse transcriptase (RT) and protease (PR) has appeared. Diketo acid (DKA) inhibitors are potent and selective inhibitors of HIV-1 IN: however the action mechanism is not well understood. Here, to study the inhibition mechanism of DKAs we performed 10 ns comparative molecular dynamics simulations on HIV-1 IN bound with three most representative DKA inhibitors: Shionogi inhibitor, S-1360 and two Merck inhibitors L-731,988 and L-708,906. Our simulations show that the acidic part of S-1360 formed salt bridge and cation-π interactions with Lys159. In addition, the catalytic Glu152 in S-1360 was pushed away from the active site to form an ion-pair interaction with Arg199. The Merck inhibitors can maintain either one or both of these ion-pair interaction features. The difference in potencies of the DKA inhibitors is thus attributed to the different binding modes at the catalytic site. Such structural information at atomic level, not only demonstrates the action modes of DKA inhibitors but also provides a novel starting point for structural-based design of HIV-1 IN inhibitors.
    Citation
    Huang, M., Grant, G.H., Richards, W.G. (2011) 'Binding modes of diketo-acid inhibitors of HIV-1 integrase: a comparative molecular dynamics simulation study', Journal of molecular graphics & modelling 29 (7):956-64
    Publisher
    Elsevier
    Journal
    Journal of molecular graphics & modelling
    URI
    http://hdl.handle.net/10547/228932
    DOI
    10.1016/j.jmgm.2011.04.002
    PubMed ID
    21531158
    PubMed Central ID
    PMC3101338
    Additional Links
    https://www.sciencedirect.com/science/article/pii/S1093326311000519
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101338/
    Type
    Article
    Language
    en
    ISSN
    1873-4243
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.jmgm.2011.04.002
    Scopus Count
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