Structure-based design modifications of the paullone molecular scaffold for cyclin-dependent kinase inhibition

A congeneric series of paullones were characterized using a 3-D QSAR with c yclin-dependent kinase 1 (CDK1) inhibition data. A homology model of CDK1-c yclin B was developed from the crystal structure of CDK2-cyclin A, which su bsequently served as the basis for the structure-based design, Paullones we re docked into the ATP binding site of the CDK1-cylin B models and were opt imized with molecular mechanics. Hydropathic analysts of the paullone-CDK1 complexes were performed after the atom types were assigned based on each l igand's electronic properties calculated from quantum mechanics. Hydropathi c descriptors formed a significant multiple regression equation that predic ts paullone IC50 data. The results indicate that the combination of hydropa thic descriptors with molecular mechanics geometries are sufficient to desi gn overt steric and chemical complementarity of the ligands, However, the e lectronic properties derived from quantum mechanics helped direct synthetic chemistry efforts to produce ligands that promote butter charge transfer a nd strengthen hydrogen bonding as facilitated by resonance stabilization, C ompounds with low affinity for CDK1,were poor charge accepters and made les s than ideal hydrogen bonding arrangements with the receptor. These conside rations 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 whic h also had similar potency in enzyme inhibition as well as a favorable anti -proliferative activity profile in living cells.