Inhibition of Plasmodium falciparum Hsp90 Contributes to the Antimalarial Activities of Aminoalcohol-carbazoles

Malaria caused by the protozoan parasite Plasmodium
falciparum (Pf) remains a major public
health problem throughout the developing world. One molecular target
that should receive more attention is the molecular chaperone Hsp90.
It is essential and highly conserved in all eukaryotes, including
in protozoan parasites. We have identified an amino-alcohol carbazole
(N-CBZ) as a PfHsp90-selective inhibitor by virtually docking a large
set of antimalarial compounds, previously found in a phenotypic screen,
into a PfHsp90-specific pocket. By correlating the ability of 30 additional
N-CBZ derivatives to bind directly to PfHsp90 with their Pf-inhibitory activity, we found that these types of compounds are
more likely to inhibit Pf growth if they bind PfHsp90.
For plausible targets such as PfHsp90, our workflow may help identifying
the molecular target for compounds found by screening large chemical
libraries for a desired biological effect and, conversely, ensuring
biological effectiveness for compounds affecting a particular target.