Potent New Small-Molecule Inhibitor of Botulinum Neurotoxin Serotype A Endopeptidase Developed by Synthesis-Based Computer-Aided Molecular Design

Abstract

Botulinum neurotoxin serotype A (BoNTA) causes a life-threatening neuroparalytic disease known as botulism. Current treatment for postexposure of BoNTA uses antibodies that are effective in neutralizing the extracellular toxin to prevent further intoxication but generally cannot rescue already intoxicated neurons. Effective small-molecule inhibitors of BoNTA endopeptidase (BoNTAc) are desirable because such inhibitors potentially can neutralize the intracellular BoNTA and offer complementary treatment for botulism. Previously, we reported a serotype-selective, small-molecule BoNTAc inhibitor with a K1pp value of 3.8 0.8 M. This inhibitor was developed by lead identification using virtual screening followed by computer-aided optimization of a lead with an IC50 value of 100 m.

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Document Details

Document Type
Technical Report
Publication Date
Nov 01, 2009
Accession Number
ADA513540

Entities

People

  • Anuradha Vummenthala
  • Charles B. Millard
  • James J. Schmidt
  • Jewn G. Park
  • Jon Davis
  • Rajesh Mishra
  • Shaohua Wang
  • Yuan-Ping Pang

Organizations

  • Mayo Clinic

Tags

Communities of Interest

  • Biomedical

DTIC Thesaurus Topics

  • Amines
  • Antibodies
  • Biomedical Research
  • Chemical Synthesis
  • Chemistry
  • Computer Simulations
  • Computers
  • Diseases And Disorders
  • Inhibitors
  • Liquid Chromatography
  • Molecular Dynamics
  • Molecules
  • Proteins
  • Small Molecules
  • Therapy
  • Three Dimensional
  • United States

Fields of Study

  • Medicine

Readers

  • Critical Infrastructure Protection in CBRN and WMD Threats.
  • Molecular and Cellular Biochemistry