Identification of potential drug targets as well as development of novel antimalarial chemotherapies
with unique mode of actions due to drug resistance by Plasmodium parasites are inevitable. Falcipains
(falcipain-2 and falcipain-3) of Plasmodium falciparum, 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 Plasmodium 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, 5α-Pregna-1,20-dien-3-one (5PGA), with inhibitory activity against plasmodial 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. Interestingly, as these compounds have cholesterol-like nuclei, they and their derivatives
might be well tolerated in humans.