Rational Drug Discovery for Isoxazole Based VEGFR2 Inhibition.

Background: Inhibiting receptor-tyrosine-kinase (RTK) signalling pathways has emerged as a key focus of novel cancer therapy development. Vascular endothelial growth factor receptor (VEGFR) is a member of the RTK family and is required for vasculogenesis and angiogenesis. Because VEGFR 2 is the subtype responsible for cellular angiogenesis and vasculogenesis, blocking it will impair tumour cell blood supply, reducing their development, proliferation, and metastasis.

Aim & objective: The aim of this study is to obtain an optimised pharmacophore as a VEGFR2 inhibitor using QSAR investigations. This aids in determining the link between structure and activity in new chemical entities (NCEs).

Materials and methods: The multi-linear regression approach (MLR) method was utilised to generate the QSAR Model using the programme QSARINS v.2.2.4.

Results and discussion: For 2D QSAR, the best models produced has correlation coefficients of R2= 0.9396. The 3D-QSAR model obtained with R2= 0.9121 and Q2 = 0.8377. Taking docking observations, pharmacological behaviour, and toxicity analyses into account, most of the derivatives demonstrated VEGFR2 inhibitory competence.

Conclusion: According to QSAR studies, more electron-donating groups on the benzene ring linked to the isoxazole were shown to be necessary for activity. In molecular docking studies, most compounds have shown stronger affinity for the crucial amino acids Cys:919, Asp:1046, and Glu:885, which are found in typical drugs. All NCEs passed the Lipinski screening.