Small molecule inhibitors of HIVgp41 N-heptad repeat trimer formation

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Allen, William J.¹  Yi, Hyun Ah²  Gochin, Miriam^3,4  Jacobs, Amy²  Rizzo, Robert C.^1,5,6 

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

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

[3] Touro Univ Calif, Dept Basic Sci, Vallejo, CA 94592 USA

[4] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA

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

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

关键词: HIV;    gp41;    Docking;    Virtual screening;    Footprint similarity;    DOCK;   

DOI  :  10.1016/j.bmcl.2015.04.067

来源: Elsevier

【 摘 要 】

Identification of mechanistically novel anti-HIV fusion inhibitors was accomplished using a computeraided structure-based design approach with the goal of blocking the formation of the N-heptad repeat (NHR) trimer of the viral protein gp41. A virtual screening strategy that included per-residue interaction patterns (footprints) was employed to identify small molecules compatible with putative binding pockets at the internal interface of the NHR helices at the core native viral six-helix bundle. From a screen of similar to 2.8 million compounds using the DOCK program, 120 with favorable energetic and footprint overlap characteristics were purchased and experimentally tested leading to two compounds with favorable cell-cell fusion (IC50) and cytotoxicity profiles. Importantly, both hits were identified on the basis of scores containing footprint overlap terms and would not have been identified using the standard DOCK energy function alone. To our knowledge, these compounds represent the first reported small molecules that inhibit viral entry via the proposed NHR-trimer obstruction mechanism. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

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