In-vitro and in-silico screening of amino acid based-cholesteryl esters: comparative investigation to explore possible triple-negative breast cancer targets

Abstract Background Inadequate selectivity, toxicity, high costs, low bioavailability, and susceptibility to drug resistance are all therapeutic limitations associated with resistant breast cancer treatments. Therefore, the present challenge is to develop highly effective anti-breast cancer targets. Within this context, the current study aims to develop amino acid-based cholesteryl ester complexes (AACE) for targeting triple-negative breast cancer cells (MDA-MB-231). Results The results of in vitro cytotoxicity for AACE (PHC, PRC, VAC) complexes on triple-negative breast carcinoma (MDA-MB-231), lung cancer (A549), and normal breast cells (MCF-10A) revealed significant potency and selectivity against MDA-MB-231 cells (IC 50 PHC = 32.58 μM, PRC = 42.76 μM, VAC = 59.23 μM) and good cytocompatibility over normal breast cells (MCF-10A) compared to erlotinib. All of the complexes demonstrated a lower cytotoxic impact on A549 cells (lung cancer) compared to erlotinib. The most cytotoxic complex, PHC, showed good DNA cleavage ability. Moreover, PHC and PRC complexes, along with erlotinib, showed hemocompatibility in the concentration range of 3.125-50 μM but revealed mild hemolytic toxicity at high concentrations (100 μM). Molecular docking analysis (3EQM-PHC = -9.16, 3EQM-PRC = − 9.55 kcal/mol; 1M17-PHC = − 8.39, 1M17-PRC = − 8.84 kcal/mol) revealed strong binding interactions of aromatase and EGFR proteins with all the complexes. Additionally, DFT studies showed a good correlation between ∆E values (PHC = 5.811 eV, PRC = 6.2563 eV), suggesting the good bioactivity of PHC. All complexes showed compliance with drug-likeness and ADMET requirements. Conclusions The results of cytotoxicity (MDA-MB-231), biocompatibility (MCF-10A), DNA cleavage, in vitro hemolysis, DFT, molecular docking, and ADMET evaluations indicate the significant potential of PHC as a possible target for resistant breast cancer cells (MDA-MB-231). Graphical Abstract