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© Research
Publication : Frontiers in pharmacology

Structure-Based Screening of Plasmodium berghei Glutathione S-Transferase Identifies CB-27 as a Novel Antiplasmodial Compound.

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Frontiers in pharmacology - 01 Jan 2020

Colón-Lorenzo EE, Colón-López DD, Vega-Rodríguez J, Dupin A, Fidock DA, Baerga-Ortiz A, Ortiz JG, Bosch J, Serrano AE,

Link to Pubmed [PMID] – 32256353

Link to DOI – 10.3389/fphar.2020.00246

Front Pharmacol 2020 ; 11(): 246

Plasmodium falciparum parasites are increasingly drug-resistant, requiring the search for novel antimalarials with distinct modes of action. Enzymes in the glutathione pathway, including glutathione S-transferase (GST), show promise as novel antimalarial targets. This study aims to better understand the biological function of Plasmodium GST, assess its potential as a drug target, and identify novel antiplasmodial compounds using the rodent model P. berghei. By using reverse genetics, we provided evidence that GST is essential for survival of P. berghei intra-erythrocytic stages and is a valid target for drug development. A structural model of the P. berghei glutathione S-transferase (PbGST) protein was generated and used in a structure-based screening of 900,000 compounds from the ChemBridge Hit2Lead library. Forty compounds were identified as potential inhibitors and analyzed in parasite in vitro drug susceptibility assays. One compound, CB-27, exhibited antiplasmodial activity with an EC50 of 0.5 μM toward P. berghei and 0.9 μM toward P. falciparum multidrug-resistant Dd2 clone B2 parasites. Moreover, CB-27 showed a concentration-dependent inhibition of the PbGST enzyme without inhibiting the human ortholog. A shape similarity screening using CB-27 as query resulted in the identification of 24 novel chemical scaffolds, with six of them showing antiplasmodial activity ranging from EC50 of 0.6-4.9 μM. Pharmacokinetic and toxicity predictions suggest that the lead compounds have drug-likeness properties. The antiplasmodial potency, the absence of hemolytic activity, and the predicted drug-likeness properties position these compounds for lead optimization and further development as antimalarials.

https://pubmed.ncbi.nlm.nih.gov/32256353