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

Abstract

Angiogenesis plays a pivotal role in the growth, survival, and metastasis of solid tumors, with Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) being overexpressed in many human solid tumors, making it an appealing target for anti-cancer therapies. This study aimed to identify potential lead compounds with azole moiety exhibiting VEGFR-2 inhibitory effects. A ligand-based pharmacophore model was constructed using the X-ray crystallographic structure of VEGFR-2 complexed with tivozanib (PDB ID: 4ASE) to screen the ZINC15 database. Following virtual screening, six compounds demonstrated promising docking scores and drug-likeness comparable to tivozanib. These hits underwent detailed pharmacokinetic analysis to assess their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Furthermore, Density Functional Theory (DFT) analysis was employed to investigate the molecular orbital properties of the top hits from molecular docking. Molecular dynamics (MD) simulations were conducted to evaluate the conformational stability of the complexes over a 100 ns run. Results indicated that the compounds (ZINC8914312, ZINC8739578, ZINC8927502, and ZINC17138581) exhibited the most promising lead requirements for inhibiting VEGFR-2 and suppressing angiogenesis in cancer therapy. This integrated approach, combining pharmacophore modeling, molecular docking, ADMET studies, DFT analysis, and MD simulations, provides valuable insights into the identification of potential anti-cancer agents targeting VEGFR-2.

Keywords

• molecular docking
• molecular dynamics simulation
• virtual screening
• Computer-Aided Drug Design (CADD)
• receptor tyrosine kinases (RTKs)