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Bioorg Med Chem Lett. 2017 Jul 15;27(14):3177-3184. doi: 10.1016/j.bmcl.2017.05.020. Epub 2017 May 8.

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

Author information

1
Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, NY 11794, United States.
2
Department of Microbiology and Immunology, State University of New York at Buffalo, Buffalo, NY 14214, United States.
3
Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, NY 11794, United States; Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States; Laufer Center for Physical & Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, United States. Electronic address: rizzorc@gmail.com.

Abstract

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=37.81µM), 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.

KEYWORDS:

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

PMID:
28558972
PMCID:
PMC5551449
DOI:
10.1016/j.bmcl.2017.05.020
[Indexed for MEDLINE]
Free PMC Article

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