De Novo Discovery of Serotonin N -Acetyltransferase Inhibitors

Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, Maryland, United States
Journal of Medicinal Chemistry (Impact Factor: 5.45). 12/2007; 50(22):5330-8. DOI: 10.1021/jm0706463
Source: PubMed


Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) is a member of the GCN5 N-acetyltransferase (GNAT) superfamily and catalyzes the penultimate step in the biosynthesis of melatonin; a large daily rhythm in AANAT activity drives the daily rhythm in circulating melatonin. We have used a structure-based computational approach to identify the first druglike and selective inhibitors of AANAT. Approximately 1.2 million compounds were virtually screened by 3D high-throughput docking into the active site of X-ray structures for AANAT, and in total 241 compounds were tested as inhibitors. One compound class, containing a rhodanine scaffold, exhibited low micromolar competitive inhibition against acetyl-CoA (AcCoA) and proved to be effective in blocking melatonin production in pineal cells. Compounds from this class are predicted to bind as bisubstrate inhibitors through interactions with the AcCoA and serotonin binding sites. Overall, this study demonstrates the feasibility of using virtual screening to identify small molecules that are selective inhibitors of AANAT.

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    • "65 As well as inhibiting PI3K, thiazolidinedione derivatives are clinically used PPARγ agonists (pioglitazone, rosiglitazone) and aldose reductase inhibitors (epalrestat), and have research applications as antibacterial, antimalarial, anti-inflammatory, antiviral, herbicidal, insecticidal, antifungal, anticancer, anthelmintic agents, and for the treatment of Alzheimer’s disease, central nervous systems (CNS) disorders, diabetes, cardiovascular, cystic fibrosis and thrombocytopenia.63, 66 They bind to targets as diverse as G protein-coupled receptor 40 (GPR40),67 protein tyrosine phosphatase 3 (PRL-3),68 cyclooxygenase 2 (COX-2),69 the peptidoglycan biosynthesis enzymes, MurB, MurC and MurG,63 B cell lymphoma-2 (Bcl-2),70 phosphodiesterase 4 (PDE4),71 fungal protein mannosyl transferase 1 (PMT1),72 tumor necrosis factor alpha (TNF-α),73 hepatitis C virus nonstructural protein 3 (HCV NS3) and NS5b polymerase (HCV NS5b),74, 75 cytosolic phospholipase A2α (cPLA2α),76 proto-oncogene serine/threonine protein kinase (Pim-1),77 cyclin-dependent kinase 2 (CDK2),54 HIV-1 integrase,78 serotonin N-acetyltransferase (AANAT),79 and glycogen synthase kinase-3β (GSK-3β).80 Several of the most potent compounds identified here have also been picked up in other screening campaigns, offering a cautionary note to the possibility of off-target effects. "
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