Discovery and optimization of novel small-molecule HIV-1 entry inhibitors using field-based virtual screening and bioisosteric replacement

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Tuyishime, Marina¹  Danish, Matt¹  Princiotto, Amy²  Mankowski, Marie K.³  Lawrence, Rae⁴  Lombart, Henry-Georges⁵  Esikov, Kirill⁵  Berniac, Joel⁵  Kuang Liang⁶  Ji Jingjing⁶  Ptak, Roger G.³  Madani, Navid²  Cocklin, Simon¹ 

[1] Drexel Univ, Coll Med, Dept Biochem & Mol Biol, Philadelphia, PA 19104 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA

[3] So Res Inst, Dept Infect Dis Res, Frederick, MD 21701 USA

[4] Cresset, Litlington, Cambs, England

[5] AsisChem Inc, Watertown, MA 02472 USA

[6] HD Biosci Co Ltd, Shanghai 201201, Peoples R China

关键词: Field-based virtual screening;    Three-dimensional virtual screening;    HIV-1 Env;    Antiviral;    Bioisostere;    Entry inhibitor;    Field-based scaffold hopping;   

DOI  :  10.1016/j.bmcl.2014.10.027

来源: Elsevier

【 摘 要 】

With the emergence of drug-resistant strains and the cumulative toxicities associated with current therapies, demand remains for new inhibitors of HIV-1 replication. The inhibition of HIV-1 entry is an attractive, yet underexploited therapeutic approach with implications for salvage and preexposure prophylactic regimens, as well as topical microbicides. Using the combination of a field-derived bioactive conformation template to perform virtual screening and iterative bioisosteric replacements, coupled with in silico predictions of absorption, distribution, metabolism, and excretion, we have identified new leads for HIV-1 entry inhibitors. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

Free