Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity

Ashutosh Tripathi, Micaela Fornabaio, Glen E. Kellogg, John T. Gupton, David A. Gewirtz, W. Andrew Yeudall, Nina E. Vega, Susan L. Mooberry

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Compounds that bind at the colchicine site of tubulin have drawn considerable attention with studies indicating that these agents suppress microtubule dynamics and inhibit tubulin polymerization. Data for 18 polysubstituted pyrrole compounds are reported, including antiproliferative activity against human MDA-MB-435 cells and calculated free energies of binding following docking the compounds into models of αβ-tubulin. These docking calculations coupled with HINT interaction analyses are able to represent the complex structures and the binding modes of inhibitors such that calculated and measured free energies of binding correlate with an r2 of 0.76. Structural analysis of the binding pocket identifies important intermolecular contacts that mediate binding. As seen experimentally, the complex with JG-03-14 (3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester) is the most stable. These results illuminate the binding process and should be valuable in the design of new pyrrole-based colchicine site inhibitors as these compounds have very accessible syntheses.

Original languageEnglish (US)
Pages (from-to)2235-2242
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number5
DOIs
StatePublished - Mar 1 2008

Keywords

  • Antitubulin
  • Cytotoxicity
  • HINT
  • Molecular docking
  • Pyrroles

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Tripathi, A., Fornabaio, M., Kellogg, G. E., Gupton, J. T., Gewirtz, D. A., Yeudall, W. A., Vega, N. E., & Mooberry, S. L. (2008). Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity. Bioorganic and Medicinal Chemistry, 16(5), 2235-2242. https://doi.org/10.1016/j.bmc.2007.11.076