Computer aided docking of small molecules to the active site of the malarial aspartic protease, Plasmepsin II

Malaria afflicts nearly 500 million people annually and kills about 2 million of them. The pathogenic organisms plasmodium falciparum and Plasmodium vivax are responsible for most infections and deaths and they are becoming increasingly resistant to drugs, making it essential to identify new antimalarial agents. Proteases are attractive candidates for drug development because they play a vital role in parasite metabolism. Haemoglobin degradation is a metabolic process that is central to the growth and maturation of the malaria parasite. Two aspartic proteases from Plasmodium falciparum Plasmepsin (Plm) I and II that initiate degradation of haemoglobin have been identified and characterized. In this paper, the haemoglobin degrading enzyme Plm II is used as the target macromolecule. Computer assisted database search was used to dock molecules into the active site of Plm II using the computer software Dock version 4. Docked compounds were ranked according to their interaction energy score with the active site and the binding energy of some selected compounds were calculated using the computer software MOLARIS. In order to check the selectivity of the selected compounds they were docked into a similar enzyme, cathepsin D found in humans and their binding energies were also calculated. Based on the difference in binding energy values, eighteen compounds were identified as potential antimalarial drug leads.

Keywords: Binding free energy change, Cathepsin D, DOCK v4, malaria, MOLARIS, Plasmepsin II, 3D database  

doi:10.4038/jnsfsr.v36i2.150

Journal of the National Science Foundation of Sri Lanka 36 (2) 171-178