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.

由原虫寄生虫恶性疟原虫（P. falciparum，简称 Pf）引起的疟疾在发展中国家仍然是一个重大的公共卫生问题。在众多应当受到更多关注的分子靶点中，分子伴侣热休克蛋白 90（Hsp90）显得尤为关键。它在所有真核生物中，包括原虫寄生虫中，均表现出至关重要的功能和高度保守性。我们通过将大量先前在表型筛选中发现的抗疟药物虚拟对接到 PfHsp90 特异性口袋中，成功鉴定了一种氨基醇咔唑（N-CBZ）作为 PfHsp90 选择性抑制剂。通过将 30 种额外的 N-CBZ 衍生物直接与 PfHsp90 结合的能力与其对 Pf 的抑制作用相关联，我们发现，若此类化合物能够结合 PfHsp90，则更有可能抑制 Pf 的生长。针对此类具有潜在靶点的分子，如 PfHsp90，我们的工作流程有助于识别通过筛选大量化学库以获得特定生物学效应的化合物所对应的分子靶点，反之亦然，确保影响特定靶点的化合物具有生物学有效性。