Discovery of Novel Multiangiogenic Agents Targeting VEGFR2, EphB4, FGFR-1, and TIE-2: Receptor-Based Pharmacophore Modeling, Virtual Screening, and Molecular Modeling Studies

Abstract

The angiogenesis phenomenon is crucial for the formation of new blood vessels in cancer cells. The cancerous cells’ progress hampers other healthy cells. The main objective of this study is to explore and decipher multimodal natural compounds against VEGFR2, EphB4, FGFR-1, and TIE-2 drug targets to arrest angiogenesis and progression. The receptor-based pharmacophore modeling of VEGFR2, EphB4, FGFR-1, and TIE-2 was developed and validated through enrichment parameters. Further, the validated hypothesis allowed for screening druglike natural product databases such as SuperNatural 3.0, COCONUT, and LOTUS. The common pharmacophoric featured natural compounds were assessed for binding affinities using absolute end-point methods. Finally, density functional theory has been studied to understand the chemical reactivity and stability of the protein complexes. Among all of the screened natural compounds, 17 natural compounds were found to align accurately against validated pharmacophore models having higher fitness scores and align scores. Taking reference drugs sorafenib (VEGFR2), NVP-BHG712 (EphB4), pemiganitib (FGFR-1), and DP1919 (TIE-2), three promising natural compounds CNP0003920, CNP0243075, and CNP0211397 were concluded based on their end-point binding energies, binding interactions, molecular dynamics, and optimal pharmacokinetic and toxicity profiles. The density functional theory (DFT) results suggested that the identified compounds bound with protein complexes are stable. Our findings can represent a promising starting point for developing multimodal analogues VEGFR2, EphB4, FGFR-1, and TIE-2 proteins.