Directing Cancer-Related Angiogenesis: Progressive E-Pharmacophore Modelling of Novel Selective VEGFR-1 Inhibitors
Abstract
B
ackground:Vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor that plays a key role in angiogenesis signalling. Development of selective VEGFR-1 inhibitors represents a promising anti-angiogenic therapeutic strategy for cancer treatment. However, design of selective VEGFR-1 inhibitors remains challenging.
Methodology: The crystal structure of VEGFR-1 kinase domain bound to an inhibitor (PDB: 3HNG) was pre-processed using Protein Preparation Wizard tools in Schrodinger. Missing loops were modelled and hydrogen atoms added at pH 7.0. Minimization gently refined the structure. A receptor-based pharmacophore model was developed using Phase to elucidate geometry and physicochemical requirements for inhibition based on the complex structure.
Results: Database screening was conducted by flexibly fitting 896 lead-like compounds from PubChem onto the pharmacophore and scoring for optimal alignment. Top-scoring hits were docked into the VEGFR-1 binding site using Glide SP precision protocol, allowing ligand flexibility. Affinity was predicted via physics-based scoring functions. Pharmacophore screening retrieved hits that complemented critical hydrophobic and hydrogen bonding elements for VEGFR-1 inhibition. Docking yielded strong predicted binding energies on par with or better than the cocrystal inhibitor with screened compound CID: 9820557 taking the lead. Specific ligand-protein interactions provided a rationale for predicted potency.
Conclusion: An integrated computational approach combining pharmacophore modelling, virtual screening, and molecular docking enabled identification of promising VEGFR-1 targeted inhibitors. Further clinical research can propose these leads to develop as more selective agents against this important anti-angiogenic target.
Keywords: VEGFR-1; Angiogenesis; Benzamide; Pharmacophore modelling; Molecular docking; Virtual screening
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DOI: http://dx.doi.org/10.62940/als.v12i4.3831
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