title: Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening.
abstract: Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer's disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening workflow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[3,2-c]quinolin-4(5H)-one inhibitor (10) with ligand efficiency (LE) of 0.3 was identified as the lead molecule. Further SAR optimization led to the discovery of several low micromolar inhibitors with good selectivity. The research represents a new class of potent ATP non-competitive CDK5/p25 inhibitors with good CDK2/E selectivity.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, MS 38677, United States.
authors.forename: Arindam
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, MS 38677, United States. Electronic address: cutler@olemiss.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Cutler
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, MS 38677, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Doerksen
authors.affiliation: National Center for Natural Products Research, University of Mississippi, MS 38677, United States.
authors.forename: Ikhlas A
authors.initials: IA
authors.lastname: Khan
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, MS 38677, United States. Electronic address: mcjsw@olemiss.edu.
authors.forename: John S
authors.initials: JS
authors.lastname: Williamson
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D016000:Cluster Analysis; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015363:Quinolones / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D016875:tau Proteins / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D015363:Quinolones; D016875:tau Proteins; D000255:Adenosine Triphosphate; D051360:Cyclin-Dependent Kinase 5
keywords: ATP non-competitive; Alzheimer’s disease; CDK5/p25 inhibitor; E-pharmacophore; Virtual screening