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

Academic Article

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 IC50 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.
  • Keywords

  • Adenosylmethionine Decarboxylase, Aminacrine, Carbon Dioxide, Computer Simulation, Computers, Crystallography, X-Ray, Drug Evaluation, Preclinical, Enzyme Inhibitors, Humans, Recombinant Proteins, Reproducibility of Results, Software, Structure-Activity Relationship
  • Digital Object Identifier (doi)

    Authorlist

  • Brooks WH; McCloskey DE; Daniel KG; Ealick SE; Secrist JA; Waud WR; Pegg AE; Guida WC
  • Start Page

  • 1897
  • End Page

  • 1905
  • Volume

  • 47
  • Issue

  • 5