Designing novel inhibitors against histone acetyltransferase (HAT: GCN5) of Plasmodium falciparum

5 years ago

Designing novel inhibitors against histone acetyltransferase (HAT: GCN5) of Plasmodium falciparum

During active proliferation phase of intra-erythrocytic cycle, the genome of P. falciparum is regulated epigenetically and evolutionary conserved parasite-specific histone proteins are extensively acetylated. The reversible process of lysine acetylation, causing transcriptional activation and its deacetylation, causing transcriptional repression is regulated by balanced activities of HATs and HDACs. They are also known to regulate antigenic variations and gametocytic conversion in P. falciparum. These histone modifying enzymes have been identified as potential targets for development of anitmalarials in literature. PfGCN5, a HAT family member of P. falciparum is predominantly involved in H3K9 acetylation. In this study, through comparative structure and sequence analysis, we elucidate differences in the catalytic pocket of PfGCN5 which can be exploited to design selective inhibitors. Through virtual screening of known antimalarials from ChEMBL bioassay database, we mapped 10 compounds with better affinity towards PfGCN5. Further, we identified 10 more novel compounds which showed remarkably better affinity towards the Plasmodium target from analogues of mapped inhibitors from ZINC database of commercially available compounds. Comparative molecular dynamics simulation study of one of the compounds (C14) complex with PfGCN5 and HsGCN5 suggested the possible reason for its selectivity. In vitro parasite growth assay in the presence of C14 showed IC50 value at lower nanomolar range (∼ 225 nM). However, no effect in mammalian fibroblast cells was observed for C14 (up to 20 μM). Further, reduced level of HAT activity of recombinant GCN5 and H3K9Ac was observed in the parasites treated with C14. Overall, this study reports 20 potential inhibitors of PfGCN5 and experimental validation of one molecule (C14) with antimalarial activity at low nanomolar range.

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DOI: S0223523417304531