Structure-based identification of inhibitors targeting obstruction of the HIVgp41 N-heptad repeat trimer

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

McGee, T. Dwight, Jr.¹  Yi, Hyun Ah²  Allen, William J.¹  Jacobs, Amy²  Rizzo, Robert C.^1,3,4 

[1] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA

[2] SUNY Buffalo, Dept Microbiol & Immunol, Buffalo, NY 14214 USA

[3] SUNY Stony Brook, Inst Chem Biol & Drug Discovery, Stony Brook, NY 11794 USA

[4] SUNY Stony Brook, Laufer Ctr Phys & Quantitat Biol, Stony Brook, NY 11794 USA

关键词: HIV;    gp41;    Docking;    DOCK;    Virtual screening;    Footprint similarity;    Hungarian similarity;    Viral entry;    Structure-based drug design;    Computer-aided drug design;   

DOI  :  10.1016/j.bmcl.2017.05.020

来源: Elsevier

【 摘 要 】

The viral protein HIVgp41 is an attractive and validated drug target that proceeds through a sequence of conformational changes crucial for membrane fusion, which facilitates viral entry. Prior work has identified inhibitors that interfere with the formation of a required six-helix bundle, composed of trimeric C-heptad (CHR) and N-heptad (NHR) repeat elements, through blocking association of an outer CHR helix or obstructing formation of the inner NHR trimer itself. In this work, we employed similarity-based scoring to identify and experimentally characterize 113 compounds, related to 2 small-molecule inhibitors recently reported by Allen et al. (Bioorg. Med. Chem Lett. 2015, 25 2853-59), proposed to act via the NHR trimer obstruction mechanism. The compounds were first tested in an HIV cell-cell fusion assay with the most promising evaluated in a second, more biologically relevant viral entry assay. Of the candidates, compound #11 emerged as the most promising hit (IC50 = 37.81 mu M), as a result of exhibiting activity in both assays with low cytotoxicity, as was similarly seen with the known control peptide inhibitor C34. The compound also showed no inhibition of VSV-G pseudotyped HIV entry compared to a control inhibitor suggesting it was specific for HIVgp41. Molecular dynamics simulations showed the predicted DOCK pose of #11 interacts with HIVgp41 in an energetic fashion (per-residue footprints) similar to the four native NHR residues (IQLT) which candidate inhibitors were intended to mimic. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

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