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Virtual screening of human 5-aminoimidazole-4-carboxamide ribonucleotide transformylase against the NCI diversity set by use of AutoDock to identify novel nonfolate inhibitors

Academic Article
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Overview

related to degree

  • Wolan, Dennis, Ph.D. in Macromolecular and Cellular Structure and Chemistry, Scripps Research 1999 - 2004

authors

  • Li, C. L.
  • Xu, L.
  • Wolan, Dennis
  • Wilson, Ian
  • Olson, Arthur

publication date

  • December 2004

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • AICAR transformylase (5-aminoimidazole-4-carboxamide ribonucleotide transformylase) is a folate-dependent activity of the bifunctional protein ATIC (AICAR transformylase and IMP cyclohydrolase) and is responsible for catalyzing the penultimate step of the de novo purine biosynthetic pathway. As such, AICAR transformylase has been proposed as a potential target for antineoplastic drug design. Virtual screening of the human AICAR transformylase active site by use of AutoDock against the NCI diversity set, a library of compounds with nonredundant pharmacophore profiles, has revealed 44 potential inhibitor candidates. In vitro inhibition assay of 16 soluble compounds from this list revealed that eight compounds with novel scaffolds, relative to the general folate template, had micromolar inhibition. Subsequent extension of docking trials on compounds with similar scaffolds from the entire NCI-3D database has unveiled 11 additional inhibitors that were confirmed by the in vitro inhibition assay. In particular, one compound, NSC30171, had nanomolar inhibition (K(i) = 154 nM, IC(50) = 600 nM) against AICAR transformylase. These 19 inhibitors serve as novel templates/scaffolds for development of more potent and specific non-folate-based AICAR transformylase inhibitors.

subject areas

  • Binding Sites
  • Enzyme Inhibitors
  • Humans
  • Hydroxymethyl and Formyl Transferases
  • Ligands
  • Phosphoribosylaminoimidazolecarboxamide Formyltransferase
  • Structure-Activity Relationship
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Identity

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm049504o

PubMed ID

  • 15615517
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Additional Document Info

start page

  • 6681

end page

  • 6690

volume

  • 47

issue

  • 27

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