Abstract
Predictive 3D-QSAR models were developed for a series of substituted ureas inhibiting Raf-1 kinase. The results of best 3D-QSAR model were compared with structure-based studies using a Raf-1 homology model in order to gain insight into the structural requirements for activity of this class of molecules.
Three-dimensional quantitative structure activity relationship (3D-QSAR) analyses were carried out on 91 substituted ureas in order to understand their Raf-1 kinase inhibitory activities. The studies include Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). Models with good predictive abilities were generated with the cross validated
r
2 (
r
cv
2
) values for CoMFA and CoMSIA being 0.53 and 0.44, respectively. The conventional
r
2 values are 0.93 and 0.87 for CoMFA and CoMSIA, respectively. In addition, a homology model of Raf-1 was also constructed using the crystal structure of the kinase domain of B-Raf isoform with one of the most active Raf-1 inhibitors (
48) inside the active site. The ATP binding pocket of Raf-1 is virtually similar to that of B-Raf. Selected ligands were docked in the active site of Raf-1. Molecule
48 adopts an orientation similar to that inside the B-Raf active site. The 4-pyridyl group bearing amide substituent is located in the adenosine binding pocket, and anchored to the protein through a pair of hydrogen bonds with Cys424 involving ring N-atom and amide NH group. The results of best 3D-QSAR model were compared with structure-based studies using the Raf-1 homology model. The results of 3D-QSAR and docking studies validate each other and provided insight into the structural requirements for activity of this class of molecules as Raf-1 inhibitors. Based on these results, novel molecules with improved activity can be designed.