In silico chemical library screening and experimental validation of a novel 9-aminoacridine based lead-inhibitor of human S-adenosylmethionine decarboxylase

Wesley H. Brooks, Diane E. McCloskey, Kenyon G. Daniel, Steven E. Ealick, John A. Secrist, William R. Waud, Anthony E. Pegg, Wayne C. Guida

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

In silico chemical library screening (virtual screening) was used to identify a novel lead compound capable of inhibiting S-adenosylmethionine decarboxylase (AdoMetDC). AdoMetDC is intimately involved in the biosynthesis of polyamines, which are essential for tumor progression and are elevated in numerous types of tumors. Therefore, inhibition of this enzyme provides an attractive target for the discovery of novel anticancer drugs. We performed virtual screening using a computer model derived from the X-ray crystal structure of human AdoMetDC and the National Cancer Institute's Diversity Set (1990 compounds). Our docking study suggested several compounds that could serve as drug candidates since their docking modes and scores revealed potential inhibitory activity toward AdoMetDC. Experimental testing of the top-scoring compounds indicated that one of these compounds (NSC 354961) possesses an IC 50 in the low micromolar range. A search of the entire NCI compound collection for compounds similar to NSC 354961 yielded two additional compounds that exhibited activity in the experimental assay but with significantly diminished potency relative to NSC 354961. In this report, we disclose the activity of NSC 354961 against AdoMetDC and its probable binding mode based on computational modeling. We also discuss the importance of virtual screening in the context of enzymes that are not readily amenable to high-throughput assays, thereby demonstrating the efficacy of virtual screening, combined with selective experimental testing, in identifying new potential drug candidates.

Original languageEnglish (US)
Pages (from-to)1897-1905
Number of pages9
JournalJournal of Chemical Information and Modeling
Volume47
Issue number5
DOIs
StatePublished - Sep 1 2007

Fingerprint

Aminacrine
Adenosylmethionine Decarboxylase
Screening
Lead
drug
candidacy
Tumors
Assays
Enzymes
Pharmaceutical Preparations
Lead compounds
cancer
Enzyme inhibition
Biosynthesis
Polyamines
Testing
Crystal structure
Throughput
X rays

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Cite this

Brooks, Wesley H. ; McCloskey, Diane E. ; Daniel, Kenyon G. ; Ealick, Steven E. ; Secrist, John A. ; Waud, William R. ; Pegg, Anthony E. ; Guida, Wayne C. / In silico chemical library screening and experimental validation of a novel 9-aminoacridine based lead-inhibitor of human S-adenosylmethionine decarboxylase. In: Journal of Chemical Information and Modeling. 2007 ; Vol. 47, No. 5. pp. 1897-1905.
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In silico chemical library screening and experimental validation of a novel 9-aminoacridine based lead-inhibitor of human S-adenosylmethionine decarboxylase. / Brooks, Wesley H.; McCloskey, Diane E.; Daniel, Kenyon G.; Ealick, Steven E.; Secrist, John A.; Waud, William R.; Pegg, Anthony E.; Guida, Wayne C.

In: Journal of Chemical Information and Modeling, Vol. 47, No. 5, 01.09.2007, p. 1897-1905.

Research output: Contribution to journalArticle

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