title: De novo design of N-(pyridin-4-ylmethyl)aniline derivatives as KDR inhibitors: 3D-QSAR, molecular fragment replacement, protein-ligand interaction fingerprint, and ADMET prediction.
abstract: Vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase VEGFR-2 or kinase insert domain receptor (KDR) have been identified as promising targets for novel anticancer agents. To achieve new potent inhibitors of KDR, we conducted molecular fragment replacement (MFR) studies for the understanding of 3D-QSAR modeling and the docking investigation of arylphthalazines and 2-((1H-Azol-1-yl)methyl)-N-arylbenzamides-based KDR inhibitors. Two favorable 3D-QSAR models (CoMFA with q(2), 0.671; r(2), 0.969; CoMSIA with q(2), 0.608; r(2), 0.936) have been developed to predict the biological activity of new compounds. The new molecular database generated by MFR was virtually screened using Glide (docking) and further evaluated with CoMFA prediction, protein-ligand interaction fingerprint (PLIF) and ADMET analysis. 44 N-(pyridin-4-ylmethyl)aniline derivatives as novel potential KDR inhibitors were finally obtained. In this paper, the work flow developed could be applied to de novo drug design and virtual screening potential KDR inhibitors, and use hit compounds to further optimize and design new potential KDR inhibitors.
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Haichun
authors.initials: H
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiao
authors.forename: Haoliang
authors.initials: H
authors.lastname: Yuan
authors.forename: Fengxiao
authors.initials: F
authors.lastname: Wang
authors.forename: Shuai
authors.initials: S
authors.lastname: Lu
authors.forename: Sihui
authors.initials: S
authors.lastname: Yao
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Ke
authors.forename: Wenting
authors.initials: W
authors.lastname: Tai
authors.forename: Yulei
authors.initials: Y
authors.lastname: Jiang
authors.forename: Yadong
authors.initials: Y
authors.lastname: Chen
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D016000:Cluster Analysis; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation / Q000379:methods; D010449:Peptide Mapping; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D008024:Ligands; C581037:N-(pyridin-4-ylmethyl)aniline; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D040301:Vascular Endothelial Growth Factor Receptor-2