2. Academic Validation
  3. Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors

Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors

  • J Med Chem. 2018 Apr 26;61(8):3582-3594. doi: 10.1021/acs.jmedchem.8b00035.
Stephen J Capuzzi 1,  Wei Sun 2,  Eugene N Muratov 1 3,  Carles Martínez-Romero 4 5,  Shihua He 6,  Wenjun Zhu 6 7,  Hao Li 2,  Gregory Tawa 2,  Ethan G Fisher 2,  Miao Xu 2,  Paul Shinn 2,  Xiangguo Qiu 6 7,  Adolfo García-Sastre 4 5 8,  Wei Zheng 2,  Alexander Tropsha 1
Affiliations

Affiliations

  • 1 Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry , UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.
  • 2 National Center for Advancing Translational Sciences , National Institutes of Health , Bethesda , Maryland 20892 , United States.
  • 3 Department of Chemical Technology , Odessa National Polytechnic University , Odessa 65000 , Ukraine.
  • 4 Department of Microbiology , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
  • 5 Global Health and Emerging Pathogens Institute , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
  • 6 Special Pathogens Program, National Microbiology Laboratory , Public Health Agency of Canada , 1015 Arlington Street , Winnipeg , Manitoba R3E 3R2 , Canada.
  • 7 Department of Medical Microbiology , University of Manitoba , 745 Bannatyne Avenue , Winnipeg , Manitoba R3E 0J9 , Canada.
  • 8 Department of Medicine, Division of Infectious Diseases , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
PMID: 29624387 DOI: 10.1021/acs.jmedchem.8b00035
Abstract

The Ebola virus (EBOV) causes severe human Infection that lacks effective treatment. A recent screen identified a series of compounds that block EBOV-like particle entry into human cells. Using data from this screen, quantitative structure-activity relationship models were built and employed for virtual screening of a ∼17 million compound library. Experimental testing of 102 hits yielded 14 compounds with IC50 values under 10 μM, including several sub-micromolar inhibitors, and more than 10-fold selectivity against host cytotoxicity. These confirmed hits include FDA-approved drugs and clinical candidates with non-antiviral indications, as well as compounds with novel scaffolds and no previously known bioactivity. Five selected hits inhibited BSL-4 live-EBOV Infection in a dose-dependent manner, including vindesine (0.34 μM). Additional studies of these novel anti-EBOV compounds revealed their mechanisms of action, including the inhibition of NPC1 protein, Cathepsin B/L, and lysosomal function. Compounds identified in this study are among the most potent and well-characterized anti-EBOV inhibitors reported to date.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z