In Silico Screening of 1,3,4-Thiadiazole Derivatives as Inhibitors of Vascular Endothelial Growth Factor Receptor-2...

Area of Science:

• Medicinal Chemistry
• Computational Drug Design
• Oncology

Background:

• Angiogenesis is crucial for tumor growth and metastasis.
• Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) is overexpressed in many solid tumors, making it a prime therapeutic target.
• Targeting VEGFR-2 offers a promising strategy for anti-cancer therapies.

Purpose of the Study:

• To identify novel lead compounds with azole moieties that inhibit VEGFR-2.
• To screen the ZINC15 database for potential VEGFR-2 inhibitors using a ligand-based pharmacophore model.
• To evaluate the drug-likeness and pharmacokinetic properties of identified compounds.

Main Methods:

• Construction of a ligand-based pharmacophore model using VEGFR-2-tivozanib complex (PDB ID: 4ASE).
• Virtual screening of the ZINC15 database, followed by molecular docking and ADMET analysis.
• Density Functional Theory (DFT) and Molecular Dynamics (MD) simulations to assess molecular properties and complex stability.

Main Results:

• Six compounds showed promising docking scores and drug-likeness comparable to tivozanib.
• Four compounds (ZINC8914312, ZINC8739578, ZINC8927502, ZINC17138581) demonstrated significant potential as VEGFR-2 inhibitors.
• The integrated computational approach provided valuable insights into lead compound identification.

Conclusions:

• The identified azole-containing compounds are promising candidates for anti-cancer drug development targeting VEGFR-2.
• These compounds have the potential to suppress tumor angiogenesis and metastasis.
• The study highlights the efficacy of combining computational methods for accelerated drug discovery.