3D-QSAR CoMFA, CoMSIA studies on substituted ureas as Raf-1 kinase inhibitors and its confirmation with structure-based studies

详细信息    查看全文

• 作者：Thaimattam ; Ram ; Daga ; Pankaj ; Rajjak ; Shaikh Abdul ; Banerjee ; Rahul ; Iqbal ; Javed
• 关键词：3D-QSAR ; Homology modeling ; Docking ; Raf-1 kinase inhibitors
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2004
• 出版时间：December 15, 2004
• 年：2004
• 卷：12
• 期：24
• 页码：6415-6425
• 全文大小：707 K

文摘

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 r² ( Formula Not Shown ) values for CoMFA and CoMSIA being 0.53 and 0.44, respectively. The conventional r² 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.