Discovery of Inhibitors To Block Interactions of HIV-1 Integrase with Human LEDGF/p75 via Structure-Based Virtual Screening and Bioassays

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• 作者：Guoping Hu ; Xi Li ; Xuan Zhang ; Yaozong Li ; Lei Ma ; Liu-Meng Yang ; Guixia Liu ; Weihua Li ; Jin Huang ; Xu Shen ; Lihong Hu ; Yong-Tang Zheng ; Yun Tang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：10108-10117
• 全文大小：524K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

This study aims to identify inhibitors that bind at the interface of HIV-1 integrase (IN) and human LEDGF/p75, which represents a novel target for anti-HIV therapy. To date, only a few such inhibitors have been reported. Here structure-based virtual screening was performed to search for the inhibitors from an in-house library of natural products and their derivatives. Among the 38 compounds selected by our strategy, 18 hits were discovered. The two most potent inhibitors showed IC₅₀ values at 0.32 and 0.26 渭M, respectively. Three compounds were subsequently selected for anti-HIV assays, among which (E)-3-(2-chlorophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one (NPD170) showed the highest antiviral activity (EC₅₀ = 1.81 渭M). The antiviral mechanism of these compounds was further explored, and the results validated that the compounds interrupted the binding of transfected IN to endogenous LEDGF/p75. These findings could be helpful for anti-HIV drug discovery.