Pharmacophore and docking-based combined in-silico study of KDR inhibitors

• Published in: Journal of molecular graphics & modelling 2009-08, Vol.28 (1), p.54-61
• Main Authors: Pasha, F.A., Muddassar, M., Neaz, M.M., Cho, Seung Joo
• Format: Article
• Language: English
• Subjects: 3D-QSAR; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; CoMFA; CoMSIA; Docking; Drug design; Humans; Models, Molecular; Molecular Structure; Pharmacophore; Protein Binding - drug effects; Protein Structure, Secondary; Pyrazolones - chemistry; Pyrazolones - pharmacology; Quantitative Structure-Activity Relationship; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; VEGFR
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2009.04.006

The growth and metastasis of solid tumors is dependent on angiogenesis. The vascular endothelial growth factor (VEGF) and its cell surface receptor in human KDR (kinase domain containing receptor or VEGFR-2) have particular interest because of their importance in angiogenesis. The development of novel inhibitors of VEGFR-2 would be helpful to check the growth of tumors. Quantitative structure activity relationship (QSAR) analyses used to understand the structural factors affecting inhibitory potency of thiazole-substituted pyrazolone derivatives. Several pharmacophore-based models indicated the importance of steric, hydrophobic and hydrogen bond acceptor groups to inhibitory activity. The comparative molecular field analyses (CoMFA) and comparative molecular similarity indices analyses (CoMSIA) based 3D-QSAR models were derived using pharmacophore-based alignment. Both CoMFA ( q 2 = 0.70, r 2 = 0.97 and r predictive 2 = 0.61 ) and CoMSIA ( q 2 = 0.54, r 2 = 0.82 and r predictive 2 = 0.66 ) gave reasonable results. The molecular docking (receptor-guided technique) with a recently reported receptor structure (PDB = 1YWN) were performed. The docked alignment was subsequently used for 3D-QSAR (CoMFA; q 2 = 0.56, r 2 = 0.97, r predictive 2 = 0.82 , CoMSIA; q 2 = 0.58 r 2 = 0.91, r predictive 2 = 0.69 ). The overall both studies were indicated, steric, electrostatic and hydrogen bond acceptor effects contribute to the inhibitory activity. CoMFA and CoMSIA models suggested that a positive bulk with hydrophobic effect is desirable around position 4 and 5 and hydrogen bond acceptor groups around pyrazolones ring will be helpful.