Dataset Information

Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-RafV600E/KDR Inhibitors Using Docking and 3D-QSAR Approaches.

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.

SUBMITTER: Liu HC

PROVIDER: S-EPMC4632759 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-RafV600E/KDR Inhibitors Using Docking and 3D-QSAR Approaches.

Liu Hai-Chun HC Tang San-Zhi SZ Lu Shuai S Ran Ting T Wang Jian J Zhang Yan-Min YM Xu An-Yang AY Lu Tao T Chen Ya-Dong YD

International journal of molecular sciences 20151015 10

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 wer ...[more]

PMID: 26501259

Similar Datasets

Project description:The aldose reductase (AR) enzyme is an important target enzyme in the development of therapeutics against hyperglycaemia induced health complications such as retinopathy, etc. In the present study, a quantitative structure activity relationship (QSAR) evaluation of a dataset of 226 reported AR inhibitor (ARi) molecules is performed using a genetic algorithm - multi linear regression (GA-MLR) technique. Multi-criteria decision making (MCDM) analysis furnished two five variables based QSAR models with acceptably high performance reflected in various statistical parameters such as, R2 = 0.79-0.80, Q2 LOO = 0.78-0.79, Q2 LMO = 0.78-0.79. The QSAR model analysis revealed some of the molecular features that play crucial role in deciding inhibitory potency of the molecule against AR such as; hydrophobic Nitrogen within 2 Å of the center of mass of the molecule, non-ring Carbon separated by three and four bonds from hydrogen bond donor atoms, number of sp2 hybridized Oxygen separated by four bonds from sp2 hybridized Carbon atoms, etc. 14 in silico generated hits, using a compound 18 (a most potent ARi from present dataset with pIC50 = 8.04 M) as a template, on QSAR based virtual screening (QSAR-VS) furnished a scaffold 5 with better ARi activity (pIC50 = 8.05 M) than template compound 18. Furthermore, molecular docking of compound 18 (Docking Score = -7.91 kcal/mol) and scaffold 5 (Docking Score = -8.08 kcal/mol) against AR, divulged that they both occupy the specific pocket(s) in AR receptor binding sites through hydrogen bonding and hydrophobic interactions. Molecular dynamic simulation (MDS) and MMGBSA studies right back the docking results by revealing the fact that binding site residues interact with scaffold 5 and compound 18 to produce a stable complex similar to co-crystallized ligand's conformation. The QSAR analysis, molecular docking, and MDS results are all in agreement and complementary. QSAR-VS successfully identified a more potent novel ARi and can be used in the development of therapeutic agents to treat diabetes.

Dataset Information

Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-RafV600E/KDR Inhibitors Using Docking and 3D-QSAR Approaches.

Publications

Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-RafV600E/KDR Inhibitors Using Docking and 3D-QSAR Approaches.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets