Clonorchis sinensis or the Chinese liver fluke is one of the most prevalent parasites affecting a major population in the oriental countries. The parasite lacks
lipid generating mechanisms but is exposed to
fatty acid rich bile in the liver. A
secretory phospholipase A2, an
enzyme that breaks down complex
lipids, is important for the growth of the parasite. The
enzyme is also implicated in the pathogenesis leading up to the hepatic
fibrosis and its complications including
cancer. The five
isoforms of this particular
enzyme from the parasite therefore qualify as potential
drug targets. In this study, a detailed structural and
ligand binding analysis of the
isoforms has been done by modeling. The overall three dimensional structures of the
isoforms are well conserved with three helices and a β-wing stabilized by four
disulfide bonds. There are characteristic differences at the
calcium binding loop, hydrophobic channel and the C-terminal domain that can potentially be exploited for
drug binding. But the most significant feature pertains to the catalytic site where the
isoforms exhibit three variations of either a
histidine-
aspartate-
tyrosine or
histidine-
glutamate-
tyrosine or
histidine-
aspartate-
phenylalanine. Molecular docking studies show that
isoform specific residues and their conformations in the substrate binding hydrophobic channel make unique interactions with certain inhibitor molecules resulting in a perfect tight fit. The proposed
ligand molecules have a predicted affinity in micro-molar to nano-molar range. Interestingly, few of the
ligand binding interaction patterns is in accordance to the phylogenetic studies to thereby establish the usefulness of evolutionary mechanisms in aiding
ligand design. The molecular diversity of the parasitic PLA2 described in this study provides a platform for
personalized medicine in the
therapeutics of
clonorchiasis.