PREDICTED DRUG LIKENESS AND MOLECULAR DOCKING STUDIES OF SOME TRANSITION METAL COMPLEXES AS INHIBITORS OF PLASMEPSIN II AND IV ENZYMES

Abstract

Despite tremendous growth in malaria chemotherapy, the malaria parasite had developed resistance to most
antimalarial drugs including artemisinin, the core compound of the best antimalarial drugs available. Hence, there is
a need to develop new antimalarial drugs. Malaria proteases have proven to be effective potential targets for malaria
chemotherapy. Most antimalarial drugs developed, target the erythrocytic stage of the Plasmodium falciparum life
cycle, however, plasmepsins II and IV act on the pre-erythrocytic liver stage and so are attractive drug targets.
Recent advances in inorganic chemistry have shown transition metal complexes to be effective therapeutic agents. A
library of 18 metal complexes was collected from the literature. The chemical structures of 18 metal complexes
(ligands) were generated and optimized using Chemdraw ultra12 and chem3D. In-silico pharmacokinetics
parameters were evaluated using SwissADME online server. Crystal structures of plasmepsin II (PDB ID: 5YIB)
and IV (PDB ID: 1IS5) were collected from the protein data bank. They were prepared using Chimera and Autodock
tools. Cygwin64 terminal was used to dock the ligands into the active site of the two targets. Post-docking analysis
was performed with Chimera and Discovery Studio. All the metal complexes have shown favorable
pharmacokinetics profile. One of the ‘druggable’ ligands coded Lig6 was found to have a higher binding affinity (-
8.6 kcal / mol) to plasmepsin II than the native ligand, pepstatin A (-8.4 kcal / mol). For plasmepsin IV, Lig12 has
the best binding affinity (-8.2 kcal / mol) compared with its native ligand (-5.6 kcal / mol). Therefore, Lig6 and
Lig12 are potential antimalarial drug candidates and can be further investigated.