Footprint-based identification of viral entry inhibitors targeting HIVgp41

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• 作者：Patrick M. Holden^a ; Harmeet Kaur^b ; Rashi Goyal^c ; Miriam Gochin^b ; ^d ; Robert C. Rizzo^a ; ^e ; ^{rizzorc@gmail.com}
• 关键词：HIVgp41 ; Virtual screening ; Structure-based drug design ; Molecular footprints ; Pose rescoring ; Docking ; DOCK
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 April, 2012
• 卷：22
• 期：8
• 页码：3011-3016
• 文件大小：995 K

摘要

A targeted virtual screen to the N-helix hydrophobic pocket on HIVgp41 was performed using DOCK followed by re-ranking with a new footprint-based scoring function which employed native gp41 C-helix residues as a reference. Of ca. 500,000 small molecules screened, 115 were purchased, and 7 hits were identified with favorable binding (K_i), cell-cell fusion (IC₅₀), and cytotoxicity (CC₅₀) profiles. Three of the seven active compounds would not have been discovered without the use of the footprints, demonstrating the utility of the method for structure-based design when a known reference compound or substrate is available.