Khoza, Sanele2026-10-132026-10-132025https://hdl.handle.net/10566/25561Cardiovascular diseases (CVDs) are the primary cause of disability and death in humans worldwide. Therefore, it is necessary to continue developing new therapeutic approaches to combat CVDs. This study aimed to use in silico and in vitro models to identify compounds from South African medicinal plants that could inhibit Cathepsin S (CatS) activity. Methods: Compounds previously reported to be isolated from Asystasia gangetica, Hypericum perforatum, and Tulbaghia violacea were identified through a scoping review of the literature. Their pharmacokinetic and toxicity profiles were predicted using SwissADME, pkCSM, and ProTox-II, followed by molecular docking against CatS. A fluorescence-based enzyme assay was used to evaluate CatS inhibitory effects by quercetin, chlorogenic acid, and procyanidin at different concentrations (1-50 μg/ml). Using similar concentrations, the cytotoxicity of these compounds was assessed in H9c2 cardiomyocytes using -(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. In addition, H9c2 cells were subjected to cobalt chloride (CoCl2)-hypoxia induction. Thereafter, Oil Red O staining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA) were performed to evaluate the therapeutic effect of the selected compounds.enCardiovascular diseaseCathepsin SDrug-likenessH9c2 cell lineInhibitorsThesis