Anti-breast cancer potential of a new xanthine derivative: In silico, antiproliferative, selectivity, VEGFR-2 inhibition, apoptosis induction and migration inhibition studies

Abstract

Background: The overexpression of VEGFR-2 receptors in breast cancer provides a valuable approach to anticancer strategies. Targeting VEGFR-2, a new semisynthetic compound (T-1-MCPAB) has been designed.

Methods: Computational methods (ADMET, toxicity, DFT, Molecular Docking, Molecular Dynamics Simulations, MM-GBSA, PLIP, and PCAT) were conducted. In addition to the semi-synthesis, in vitro studies (anti-VEGFR-2, anti-proliferative, flow cytometry, and wound scratch assay) were employed.

Results: ADME and toxicity profiles of T-1-MCPAB studies indicated its overall drug-likeness showing results much better than Sorafenib. Then, T-1-MCPAB's exact 3D structure, stability, and reactivity were evoked by the DFT calculations. Molecular docking, molecular dynamics simulations, MM-GPSA, PLIP, and PCAT studies denoted the correct binding and inhibiting potential of T-1-MCPAB, towards VEGFR-2 protein. After the semisynthesis, T-1-MCPAB inhibited VEGFR-2 with an IC₅₀ of 0.135 µM, which was comparable to sorafenib's IC₅₀ of 0.0591 µM. T-1-MCPAB also showed a notable performance against MCF7 and T47D breast cancer cell lines with IC₅₀ values of 30.95 µM and 63.64 µM, respectively, and had high selectivity index values of 3.7 and 1.8, respectively. Furthermore, T-1-MCPAB influenced early and late apoptosis and significantly decreased the potential of MCF7 cells to heal and migrate.

Conclusion: T-1-MCPAB is a promising VEGFR-2 inhibitor with potential for breast cancer treatment. Further chemical and biological studies are needed to explore its potential as a therapeutic agent.

Keywords: ADMET; Breast cancer; DFT; MD simulations; PCAT; Semi synthesis; Theobromine derivatives; VEGFR-2 inhibitors.