Pharmacophore Modeling, Virtual Screening, Docking, 3D QSAR Study and Synthesis of Potential VEGFR Inhibitors For Anti-Cancer Therapy

Abstract

VEGF (vascular endothelial growth factor) plays a pivotal role in angiogenesis and vasculogenesis. Angiogenesis is required for the progression of tumors from a benign to a malignant phenotype and for metastasis. Malignant tumor cells secrete factors such as vascular endothelial growth factor (VEGF), which bind to their cognate receptors on endothelial cells to induce angiogenesis. Promising compounds from literature were selected for the generation of a pharmacophore using GALAHAD (Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Datasets) module of SYBYL X 1.3. GALAHAD generated 20 models from which one model was selected based on validation. Validation was performed using Receiver operating characteristic curve methodology. An area under the ROC curve was obtained as 0.766. A four feature pharmacophore model consisting of a hydrogen bond donor, a hydrogen bond acceptor and two hydrophobic groups was selected. On the basis of this pharmacophoric model virtual screening of selected query from NCI database was carried out. From the retrieved compounds, compounds which were having Qfit value higher than 95 were selected to design newer compounds. From the designed 10 compounds the docking study and QSAR study by CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Indices Analysis) was performed. The 5 compounds which were giving good docking score and higher predicted activity were selected for the synthesis. Synthesis of selected compounds were performed and structure prediction of synthesised compounds were performed using IR, NMR and Mass spectroscopy. In Silico ADMET property was calculated using OSIRIS property explorer. Pharmacological evaluation of synthesised compounds by cell lines study was performed using breast-MDA-MB 453 cell line.