Ligand-based pharmacophore modelling, molecular docking, and molecular dynamic studies of VEGFR2 inhibitors

Background Vascular endothelial growth factor receptor-2 (VEGFR-2) is one of the main factors that facilitate the formation of new blood vessels in tumours and has been recognized as a target for treatment of ovarian cancer and other solid tumours. Targeting VEGFR-2 remains crucial even with the number of inhibitors available since it is still the basis for the new ones which through their structural diversity and/or different mechanisms may present better potency and safety profile. Methods By employing an integrated in silico approach, a hidden denatured mechanism was accomplished in the study to explore the probable bioactivity of the phytochemicals for the VEGR-2 inhibitors. The in-ligand fashion was a pharmacophore that was developed based on a group of active VEGFR-2 inhibitors and subsequently refined into a four-feature model with superior predictive ability represented by the AUC and EF₁%. The screening process received input from numerous phytochemicals through the use of a validated pharmacophore model. Results The screening identified ZINC14583344, ZINC95099115, and ZINC85852162 as potential candidate molecules based on their impressive docking results. These hits occupied the ATP-binding pocket of VEGFR-2 and made important contacts with Asp1046, Glu885, and Cys919, which are the key residues in the binding site. The stability of the complexes was confirmed through MD simulations while the binding free energy calculations from MM-GBSA also indicated that the binding was energetically favourable. Conclusions Hence, the present work unveiled three potential phytochemical scaffolds that were predicted to act as VEGFR-2 inhibitors. The study also proposes a robust multilevel computational framework for the de novo design of anti-angiogenic drugs which may ultimately lead to faster drug discovery.