Integrated computational and biological evaluations of newly synthesized thiadiazole-based VEGFR-2 inhibitors with targeted anti-breast cancer activity

Abstract

The development of novel VEGFR-2 inhibitors remains a promising strategy for targeted breast cancer therapy, particularly against aggressive triple-negative breast cancer subtype. In this study, a series of thiadiazole derivatives were designed, synthesized, and biologically evaluated for their anti-proliferative activity against MDA-MB-231 and MCF-7 breast cancer cell lines. Among them, compound 7 exhibited superior cytotoxicity (IC₅₀ = 5.69 µM for MDA-MB-231) and demonstrated remarkable selectivity over normal cell lines. It also displayed potent VEGFR-2 inhibitory activity (IC₅₀ = 0.083 µM), comparable to the reference drug sorafenib (IC₅₀ = 0.1 µM). Mechanistic studies revealed that compound 7 induces G2/M phase arrest and promotes late-stage apoptosis, supported by enhanced caspase-3 activation, Bax upregulation, and Bcl-2 suppression. Comprehensive computational analyses-including molecular docking, molecular dynamics (MD) simulations, MM-GBSA binding free energy calculations, ProLIF interaction mapping, and PCA studies-validated the stable and effective binding of compound 7 within the ATP-binding pocket of VEGFR-2. Additionally, density functional theory (DFT) calculations supported the compound's high chemical stability and favorable electronic reactivity. Finally, in silico ADMET and toxicity predictions indicated favorable drug-likeness, low mutagenicity, and a high safety margin. Collectively, these findings position compound 7 as a potent and selective VEGFR-2 inhibitor, with promising therapeutic potential in breast cancer management and a strong foundation for further preclinical development.

Keywords: In vitro; Breast cancer; MD Simulations; Molecular docking; Thiadiazole derivatives; VEGFR-2.