Pyrrole-based antitubulin agents: Two distinct binding modalities are predicted for C-2 analogues in the colchicine site

Chenxiao Da, Nakul Telang, Peter Barelli, Xin Jia, John T. Gupton, Susan L. Mooberry, Glen E. Kellogg

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

3,5-Dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester is a promising antitubulin lead agent that targets the colchicine site of tubulin. C-2 analogues were synthesized and tested for microtubule depolymerizing and antiproliferative activity. Molecular modeling studies using both GOLD docking and HINT (Hydropathic INTeraction) scoring revealed two distinct binding modes that explain the structure-activity relationships and are in accord with the structural basis of colchicine binding to tubulin. The binding mode of higher activity compounds is buried deeper in the site and overlaps well with rings A and C of colchicine, while the lower activity binding mode shows fewer critical contacts with tubulin. The model distinguishes highly active compounds from those with weaker activities and provides novel insights into the colchicine site and compound design.

Original languageEnglish (US)
Pages (from-to)53-57
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume3
Issue number1
DOIs
StatePublished - Jan 12 2012

Keywords

  • Antitubulin
  • docking
  • hydropathic interactions
  • multifunctional pyrroles
  • structure-activity relationship

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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