Resistant Mechanism against Nelfinavir of Human Immunodeficiency Virus Type 1 Proteases 

作成者 Ode, Hirotaka, Ota, Masami, 根矢, 三郎, 畑, 昌之, Sugiura, Wataru, 星野, 忠次
作成者の別表記 Neya, Saburo, Hata, Masayuki, Hoshino, Tyuji
キーワード等 HIV-1 protease, nelfinavir, drug resistance, drug resistance, conformational change, non-active site
日本十進分類法 (NDC) 490
内容 Inhibitors against human immunodeficiency virus type-1 (HIV-1) proteases are finely effective for anti-HIV-1 treatments. However, the therapeutic efficacy is reduced by the rapid emergence of inhibitor-resistant variants of the protease. Among patients who failed in the inhibitor nelfinavir (NFV) treatment, D30N, N88D, and L90M mutations of HIV-1 protease are often observed. In spite of the serious clinical problem, it is not clear how these mutations, especially non active site mutations N88D and L90M, affect the affinity of NFV and/or why they cause the resistance to NFV. In this study, we executed molecular dynamics simulations of the NFV-bound proteases in the wild-type and D30N, N88D, D30N/N88D, L90M mutants. Our simulations clarified the conformational change at the active site of the protease and the change of the affinity with NFV for all of these mutations, even though the 88th and 90th residues are not located in the NFV-bound cavity and not able to directly interacts with NFV. D30N mutation causes the disappearance of the hydrogen bond between m-phenol group of NFV and the 30th residue. N88D mutation alters the active-site conformation slightly, and induces a favorable hydrophobic contact. L90M mutation dramatically changes the conformation at the flap region and leads to an unfavorable distortion of the binding pocket of the protease, although 90M is largely far apart from the flap region. Furthermore, the changes of binding energies of the mutants from the wild-type protease are shown to be correlated with the mutant resistivity previously reported by the phenotypic experiments.
コンテンツの種類 雑誌掲載論文 Journal Article
DCMI資源タイプ collection
掲載誌情報 Journal of Physical Chemistry B Vol.109 no.1 page.565-574 (2005)
言語 英語

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