Abstract
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.
Highlights
TM malaria vaccine has remained elusive over time[9]
Deciphering the complex biochemical pathways utilized by the Plasmodium parasites offers an array of macromolecular structures that can be targeted for antimalarial drug development[12,13,14]
Besides the poor pharmacological profiles of these peptide inhibitors, their proneness to degradation by host proteases makes them unsuitable to be used as drugs
Summary
TM malaria vaccine has remained elusive over time[9]. Recently, Mosquirix was approved by the European Medicines. Through a highly ordered cascade of reactions catalysed by a group of proteases (falcipains, plasmepsins and aspartic proteases), plasmodia break the α - and β -globin chains of the host haemoglobin into constituent amino acids[15,16,17,18] This process plays both anabolic and non-anabolic functions; a source of essential amino acids as parasites lack a de novo amino acid biosynthesis pathway as well as source of energy, the regulation of osmotic pressure and the creation of space in the host cell for the growing parasites. Considering the importance of natural products in drug discovery[21,22], our aim was to identify potential non-peptidic hits from South African (SA) natural compounds with inhibitory potency against FP-2, FP-3 and homologs from other Plasmodium species. They provide a starting point for further design of more effective derivatives
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