Understanding the structural basis for differential binding of lapachol with PfHSP70s

The 70 kDa heat shock proteins from Plasmodium falciparum (PfHSP70) are an important family of proteins that may be exploited for antimalarial design. Plant derived inhibitor ‘lapachol’ is reported to efficiently inhibit the exported PfHSP70-x while having poor activity against the parasite PfHSP70-1. In the present study, we have used in silico tools including molecular docking to understand the molecular basis for the above differences in lapachol inhibition activity against PfHSP70s. We found a significant gap in the binding energies and hence affinity of PfHSP70-1 and PfHSP70-x for lapachol with the latter having a better binding propensity. Our data highlight notable differences in the type of interactions between the two complexes. Detailed molecular analysis of the complexes has helped us to predict specific amino acid residues from both these PfHSP70 homologs that may be involved in lapachol binding. The above information may be utilized for design of PfHSP70 inhibitors with antimalarial potential.