Abstract
Research and development of multi-target inhibitors has attracted increasing attention as anticancer therapeutics. B-RafV600E synergistically works with vascular endothelial growth factor receptor 2 (KDR) to promote the occurrence and progression of cancers, and the development of dual-target drugs simultaneously against these two kinds of kinase may offer a better treatment advantage. In this paper, docking and three-dimensional quantitative structure activity relationship (3D-QSAR) studies were performed on a series of dual B-Raf/KDR inhibitors with a novel hinge-binding group, [5,6]-fused bicyclic scaffold. Docking studies revealed optimal binding conformations of these compounds interacting with both B-Raf and KDR. Based on these conformations, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models were constructed, and the best CoMFA (q2 = 0.542, r2 = 0.989 for B-Raf; q2 = 0.768, r2 = 0.991 for KDR) and CoMSIA models (q2 = 0.519, r2 = 0.992 for B-Raf; q2 = 0.849, r2 = 0.993 for KDR) were generated. Further external validations confirmed their predictability, yielding satisfactory correlation coefficients (r2pred = 0.764 (CoMFA), r2pred = 0.841 (CoMSIA) for B-Raf, r2pred = 0.912 (CoMFA), r2pred = 0.846 (CoMSIA) for KDR, respectively). Through graphical analysis and comparison on docking results and 3D-QSAR contour maps, key amino acids that affect the ligand-receptor interactions were identified and structural features influencing the activities were discussed. New potent derivatives were designed, and subjected to preliminary pharmacological evaluation. The study may offer useful references for the modification and development of novel dual B-Raf/KDR inhibitors.
Highlights
Over the past decades, the targeted therapy, which aims to develop highly selective inhibitors against a specific drug target, has become the primary paradigm in drug discovery [1,2,3]
The accuracy and reliability of the 3D-quantitative structure-activity relationship (QSAR) model is dependent on two important factors: the biological conformation selection and the structural alignment rule
To ensure molecular docking could recapture feasible conformation, Glide-SP docking algorithm was first validated by re-docking of the crystal ligand
Summary
The targeted therapy, which aims to develop highly selective inhibitors against a specific drug target, has become the primary paradigm in drug discovery [1,2,3]. B-Raf with VEGFR-2 works synergistically to promote certain cancers, and to develop multi-target drugs simultaneously against these two kinases may provide a better therapeutic advantage. To design multi-target agents, theoretical studies on the structural features of the compounds may provide useful information. Molecules with a novel hinge-binding group have been reported to show dual inhibition against both B-Raf and KDR, which form two hydrogen bond interactions with hinge region Cys amino acid residues through various [5,6]-fused bicyclic scaffolds These derivatives were proven to be the highly potent DFG-out type RAF/VEGFR-2 inhibitors. The model is expected to facilitate deeper understanding of the structure activity relationship of these compounds, and provide useful information for rational design of novel and potent dual B-Raf and KDR inhibitors
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