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

被引:14
作者
Brooks, Wesley H.
McCloskey, Diane E.
Daniel, Kenyon G.
Ealick, Steven E.
Secrist, John A., III
Waud, William R.
Pegg, Anthony E.
Guida, Wayne C. [1 ]
机构
[1] H Lee Moffitt Canc Ctr & Res Inst, Drug Discovery Program, Tampa, FL 33612 USA
[2] Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA
[3] Cornell Univ, Dept Chem & Chem Biol, Ithaca, NY 14853 USA
[4] So Res Inst, Birmingham, AL 35205 USA
[5] Univ S Florida, Coll Med, Dept Interdisciplinary Oncol, Tampa, FL 33612 USA
关键词
POLYAMINE BIOSYNTHESIS INHIBITOR; ALPHA-DIFLUOROMETHYLORNITHINE; ORNITHINE-DECARBOXYLASE; CANCER CHEMOPREVENTION; PHASE-I; SAM486A; EXCRETION; OVARIAN; GROWTH; TISSUE;
D O I
10.1021/ci700005t
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:1897 / 1905
页数:9
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