title: Computational & experimental evaluation of the structure/activity relationship of β-carbolines as DYRK1A inhibitors.
abstract: DYRK1A has been associated with Down's syndrome and neurodegenerative diseases, therefore it is an important target for novel pharmacological interventions. We combined a ligand-based pharmacophore design with a structure-based protein/ligand docking using the software MOE in order to evaluate the underlying structure/activity relationship. Based on this knowledge we synthesized several novel β-carboline derivatives to validate the theoretical model. Furthermore we identified a modified lead structure as a potent DYRK1A inhibitor (IC50=130 nM) with significant selectivity against MAO-A, DYRK2, DYRK3, DYRK4 & CLK2.
authors.affiliation: Clemens Schöpf-Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiss-Str. 4, 64287 Darmstadt, Germany.
authors.forename: Binia
authors.initials: B
authors.lastname: Drung
authors.affiliation: Clemens Schöpf-Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiss-Str. 4, 64287 Darmstadt, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Scholz
authors.affiliation: Departamento de Química, Universidade Estadual de Maringá, Avenida Colombo 53790, PR 87020-900 Maringá, Brazil.
authors.forename: Valéria A
authors.initials: VA
authors.lastname: Barbosa
authors.affiliation: Clemens Schöpf-Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiss-Str. 4, 64287 Darmstadt, Germany.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Nazari
authors.affiliation: Departamento de Química, Universidade Estadual de Maringá, Avenida Colombo 53790, PR 87020-900 Maringá, Brazil.
authors.forename: Maria H
authors.initials: MH
authors.lastname: Sarragiotto
authors.affiliation: Clemens Schöpf-Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiss-Str. 4, 64287 Darmstadt, Germany. Electronic address: schmidt_boris@t-online.de.
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
mesh_terms: D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012984:Software; D013329:Structure-Activity Relationship; D000097603:Dyrk Kinases
chemical_list: D002243:Carbolines; D008024:Ligands; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases
keywords: DYRK1A; Docking; Inhibitor; MAO-A; Pharmacophore; SAR; β-Carboline