title: Discovery of novel inhibitors of human S-adenosylmethionine decarboxylase based on in silico high-throughput screening and a non-radioactive enzymatic assay.
abstract: Natural polyamines are small polycationic molecules essential for cell growth and development, and elevated level of polyamines is positively correlated with various cancers. As a rate-limiting enzyme of the polyamine biosynthetic pathway, S-adenosylmethionine decarboxylase (AdoMetDC) has been an attractive drug target. In this report, we present the discovery of novel human AdoMetDC (hAdoMetDC) inhibitors by coupling computational and experimental tools. We constructed a reasonable computational structure model of hAdoMetDC that is compatible with general protocols for high-throughput drug screening, and used this model in in silico screening of hAdoMetDC inhibitors against a large compound library using a battery of computational tools. We also established and validated a simple, economic, and non-radioactive enzymatic assay, which can be adapted for experimental high-throughput screening of hAdoMetDC inhibitors. Finally, we obtained an hAdoMetDC inhibitor lead with a novel scaffold. This study provides both new tools and a new lead for the developing of novel hAdoMetDC inhibitors.
authors.affiliation: 1] Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China [2] College of Medical Science, China Three Gorges University, Yichang 443002, China.
authors.forename: Chenzeng
authors.initials: C
authors.lastname: Liao
authors.affiliation: 1] Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China [2] College of Medical Science, China Three Gorges University, Yichang 443002, China.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1] Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China [2] College of Medical Science, China Three Gorges University, Yichang 443002, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Tan
authors.affiliation: 1] Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China [2] College of Medical Science, China Three Gorges University, Yichang 443002, China.
authors.forename: Lidan
authors.initials: L
authors.lastname: Sun
authors.affiliation: 1] Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China [2] College of Medical Science, China Three Gorges University, Yichang 443002, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Liu
mesh_terms: D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods*; D004789:Enzyme Activation / Q000187:drug effects; D057075:Enzyme Assays / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D013053:Spectrophotometry / Q000379:methods
chemical_list: D004791:Enzyme Inhibitors; D012437:Adenosylmethionine Decarboxylase