# Validated antimalarial drug target discovery using genome-scale metabolic modeling

## TL;DR

Researchers used a genome-scale model to identify and validate a new drug target for malaria, showing how such models can aid in drug discovery.

## Contribution

This study is the first to validate a genome-scale metabolic model's predictions as a novel, druggable antimalarial target.

## Key findings

- P. falciparum UMP-CMP kinase (UCK) was identified as essential for parasite growth.
- Conditional deletion of UCK caused defective asexual growth and developmental arrest.
- UCK-selective inhibitors showed antiparasitic activity in vitro.

## Abstract

Given the rapid resistance of Plasmodium falciparum to
antimalarial drugs, there is a continual need for new treatments. A
genome-scale metabolic (GSM) model was developed with integrated
metabolomics and constraint-based, experimental flux-balance data to predict
genes essential for P. falciparum growth as drug targets.
We selected the highly ranked P. falciparum UMP-CMP kinase
(UCK) to test its necessity and the ability to inhibit parasite growth in
the presence of inhibitors. Conditional deletion mutants using the DiCre
recombinase system, generated by CRISPR-Cas genome editing, exhibited
defective asexual growth and stage-specific developmental arrest. Based on
in silico and in vitro screening,
inhibitors were identified that are selective for P.
falciparum UCK and exhibit antiparasitic activity. This study,
for the first time, shows assertions from a GSM model identifying novel,
validated “druggable” targets. These findings show a role for
GSM models in antimalarial drug discovery and identify P.
falciparum UCK as a novel, valid malaria drug target.