title: Structure-based design modifications of the paullone molecular scaffold for cyclin-dependent kinase inhibition.
abstract: A congeneric series of paullones were characterized using a 3-D QSAR with cyclin-dependent kinase 1 (CDK1) inhibition data. A homology model of CDK1-cyclin B was developed from the crystal structure of CDK2-cyclin A, which subsequently served as the basis for the structure-based design. Paullones were docked into the ATP binding site of the CDK1-cylin B models and were optimized with molecular mechanics. Hydropathic analyses of the paullone-CDK1 complexes were performed after the atom types were assigned based on each ligand's electronic properties calculated from quantum mechanics. Hydropathic descriptors formed a significant multiple regression equation that predicts paullone IC50 data. The results indicate that the combination of hydropathic descriptors with molecular mechanics geometries are sufficient to design overt steric and chemical complementarity of the ligands. However, the electronic properties derived from quantum mechanics helped direct synthetic chemistry efforts to produce ligands that promote better charge transfer and strengthen hydrogen bonding as facilitated by resonance stabilization. Compounds with low affinity for CDK1 were poor charge acceptors and made less than ideal hydrogen bonding arrangements with the receptor. These considerations led to the prediction that structures such as 9-cyanopaullone would be considerably more potent than the parent compound, a finding supported by enzyme inhibition data. Also, 9-nitropaullone emerged as a paullone which also had similar potency in enzyme inhibition as well as a favorable anti-proliferative activity profile in living cells.
authors.affiliation: Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: R
authors.initials: R
authors.lastname: Gussio
authors.forename: D W
authors.initials: DW
authors.lastname: Zaharevitz
authors.forename: C F
authors.initials: CF
authors.lastname: McGrath
authors.forename: N
authors.initials: N
authors.lastname: Pattabiraman
authors.forename: G E
authors.initials: GE
authors.lastname: Kellogg
authors.forename: C
authors.initials: C
authors.lastname: Schultz
authors.forename: A
authors.initials: A
authors.lastname: Link
authors.forename: C
authors.initials: C
authors.lastname: Kunick
authors.forename: M
authors.initials: M
authors.lastname: Leost
authors.forename: L
authors.initials: L
authors.lastname: Meijer
authors.forename: E A
authors.initials: EA
authors.lastname: Sausville
mesh_terms: D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D004791:Enzyme Inhibitors; D018844:Cyclin-Dependent Kinases