title: Multi-step virtual screening to develop selective DYRK1A inhibitors.
abstract: Developing selective inhibitors for a particular kinase remains a major challenge in kinase-targeted drug discovery. Here we performed a multi-step virtual screening for dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) inhibitors by focusing on the selectivity for DYRK1A over cyclin-dependent kinase 5 (CDK5). To examine the key factors contributing to the selectivity, we constructed logistic regression models to discriminate between actives and inactives for DYRK1A and CDK5, respectively, using residue-based binding free energies. The residue-based parameters were calculated by molecular mechanics-generalized Born surface area (MM-GBSA) decomposition methods for kinase-ligand complexes modeled by computer ligand docking. Based on the findings from the logistic regression models, we built a three-dimensional (3D) pharmacophore model and chose filter criteria for the multi-step virtual screening. The virtual hit compounds obtained from the screening were assessed for their inhibitory activities against DYRK1A and CDK5 by in vitro assay. Our screening identified two novel selective DYRK1A inhibitors with IC50values of several μM for DYRK1A and >100μM for CDK5, which can be further optimized to develop more potent selective DYRK1A inhibitors.
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address: pl11011@st2.pharm.kitasato-u.ac.jp.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Koyama
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yamaotsu
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Nakagome
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Shin-Ichiro
authors.initials: SI
authors.lastname: Ozawa
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Hayakawa
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address: hironos@pharm.kitasato-u.ac.jp.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D001681:Biological Assay; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D016015:Logistic Models; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D060388:Support Vector Machine; D000097603:Dyrk Kinases
chemical_list: D000255:Adenosine Triphosphate; D051360:Cyclin-Dependent Kinase 5; D008024:Ligands; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases
keywords: DYRK1A; Discriminant analysis; Free energy decomposition; In silico screening; Kinase selectivity