Specific Targeting of Plant and Apicomplexa Parasite Tubulin through Differential Screening Using In Silico and Assay-Based Approaches

Abstract

Dinitroanilines are chemical compounds with high selectivity for plant cell α-tubulin in which they promote microtubule depolymerization. They target α-tubulin regions that have diverged over evolution and show no effect on non-photosynthetic eukaryotes. Hence, they have been used as herbicides over decades. Interestingly, dinitroanilines proved active on microtubules of eukaryotes deriving from photosynthetic ancestors such as <i>Toxoplasma gondii</i> and <i>Plasmodium falciparum</i>, which are responsible for toxoplasmosis and malaria, respectively. By combining differential in silico screening of virtual chemical libraries on <i>Arabidopsis thaliana</i> and mammal tubulin structural models together with cell-based screening of chemical libraries, we have identified dinitroaniline related and non-related compounds. They inhibit plant, but not mammalian tubulin assembly in vitro, and accordingly arrest <i>A. thaliana</i> development. In addition, these compounds exhibit a moderate cytotoxic activity towards <i>T. gondii</i> and <i>P. falciparum</i>. These results highlight the potential of novel herbicidal scaffolds in the design of urgently needed anti-parasitic drugs.