Virtual Screening, Docking, and Designing of New VEGF Inhibitors as Anti-cancer Agents

Area of Science:

• Medicinal Chemistry
• Computational Drug Discovery
• Oncology

Background:

• Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) tyrosine kinase inhibitors are crucial in anticancer drug discovery.
• The 1H-indazole scaffold, exemplified by the FDA-approved drug AXITINIB, has demonstrated efficacy in cancer treatment.

Purpose of the Study:

• To virtually screen the PubChem library for novel VEGFR-2 kinase inhibitors.
• To design and evaluate new drug candidates based on the 1H-indazole scaffold, using AXITINIB as a reference.

Main Methods:

• Virtual screening of the PubChem database.
• Protein preparation and molecular docking analyses.
• Validation of protein structures using Ramachandran plots, ERRAT, and ProSA scores.
• Application of Lipinski's rule of five for molecular filtering.

Main Results:

• Protein validation confirmed high structural quality (Ramachandran plot: 92.1% favorable, ERRAT score: 96.24%, ProSA score: -9.24).
• Docking studies identified a lead molecule (C1) with a binding affinity of -14.08 kcal/mol, forming key hydrogen bonds with VEGFR-2 residues (Cys104, Glu108, Glu70).
• Designed molecules (M1-M4) exhibited comparable docking results to AXITINIB and favorable synthetic accessibility scores (<4.5).

Conclusions:

• Molecular docking is a viable strategy for discovering novel VEGFR-2 tyrosine kinase inhibitors.
• The identified compounds and designed molecules hold potential for the development of new anticancer therapeutics.