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Falcipains (falcipain-2 and falcipain-3) of <jats:italic>Plasmodium falciparum<\/jats:italic>, which catalyse the haemoglobin degradation process, are validated drug targets. Previous attempts to develop peptide based drugs against these enzymes have been futile due to the poor pharmacological profiles and susceptibility to degradation by host enzymes. This study aimed to identify potential non-peptide inhibitors against falcipains and their homologs from other <jats:italic>Plasmodium<\/jats:italic> species. Structure based virtual docking approach was used to screen a small non-peptidic library of natural compounds from South Africa against 11 proteins. A potential hit, 5\u03b1-Pregna-1,20-dien-3-one (5PGA), with inhibitory activity against <jats:italic>plasmodial<\/jats:italic> proteases and selectivity on human cathepsins was identified. A 3D similarity search on the ZINC database using 5PGA identified five potential hits based on their docking energies. The key interacting residues of proteins with compounds were identified via molecular dynamics and free binding energy calculations. Overall, this study provides a basis for further chemical design for more effective derivatives of these compounds. 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