title: Identification of Plasmodium falciparum spermidine synthase active site binders through structure-based virtual screening.
abstract: Seven novel binders, binding in the active site of Plasmodium falciparum spermidine synthase, were identified by structure-based virtual screening. The binding of these compounds was experimentally verified by NMR techniques. Spermidine synthase, an enzyme involved in the polyamine pathway, has been suggested as a target for treating malaria. The virtual screening protocol combined 3D pharmacophore filtering, docking, and scoring, focusing on finding compounds predicted to form interactions mimicking those of a previously known binder. The virtual screen resulted in the selection of 28 compounds that were acquired and tested from 2.6 million starting structures. Two of the seven binders were predicted to bind in the amino substrate binding pocket. Both of these showed stronger binding upon addition of methylthioadenosine, one of the two products of the enzyme, and a known binder and inhibitor. The five other compounds were predicted to bind in the part of the active site where the other substrate, decarboxylated S-adenosylmethionine, binds. These five compounds all competed for binding with methylthioadenosine.
authors.affiliation: iNovacia AB, Lindhagensgatan 133, SE-112 51 Stockholm, Sweden.
authors.forename: Micael
authors.initials: M
authors.lastname: Jacobsson
authors.forename: Magnus
authors.initials: M
authors.lastname: Gäredal
authors.forename: Johan
authors.initials: J
authors.lastname: Schultz
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
mesh_terms: D000818:Animals; D001665:Binding Sites; D016208:Databases, Factual; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000201:enzymology*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011436:Spermidine Synthase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D006574:Heterocyclic Compounds, 2-Ring; D011436:Spermidine Synthase