Computer-aided lead optimization: Improved small-molecule inhibitor of the zinc endopeptidase of botulinum neurotoxin serotype A

Jing Tang, Jewn Giew Park, Charles B. Millard, James J. Schmidt, Yuan Ping Pang

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Optimization of a serotype-selective, small-molecule inhibitor of botulinum neurotoxin serotype A (BoNTA) endopeptidase is a formidable challenge because the enzyme-substrate interface is unusually large and the endopeptidase itself is a large, zinc-binding protein with a complex fold that is difficult to simulate computationally. We conducted multiple molecular dynamics simulations of the endopeptidase in complex with a previously described inhibitor (Kiapp of 7±2.4 μM) using the cationic dummy atom approach. Based on our computational results, we hypothesized that introducing a hydroxyl group to the inhibitor could improve its potency. Synthesis and testing of the hydroxyl-containing analog as a · BoNTA endopeptidase inhibitor showed a twofold improvement in inhibitory potency (Ki app of 3.8±0.8 μM) with a relatively small increase in molecular weight (16 Da). The results offer an improved template for further optimization of BoNTA endopeptidase inhibitors and demonstrate the effectiveness of the cationic dummy atom approach in the design and optimization of zinc protease inhibitors.

Original languageEnglish (US)
Article numbere761
JournalPloS one
Volume2
Issue number8
DOIs
StatePublished - Aug 22 2007

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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