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

• Published in: Frontiers in pharmacology 2020-03, Vol.11, p.246
• Main Authors: Colón-Lorenzo, Emilee E, Colón-López, Daisy D, Vega-Rodríguez, Joel, Dupin, Alice, Fidock, David A, Baerga-Ortiz, Abel, Ortiz, José G, Bosch, Jürgen, Serrano, Adelfa E
• Format: Article
• Language: English
• Subjects: drug target; glutathione S-transferase; malaria; Pharmacology; Plasmodium berghei; shape similarity screening; structure-based screening
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2020.00246

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 GST, assess its potential as a drug target, and identify novel antiplasmodial compounds using the rodent model . By using reverse genetics, we provided evidence that GST is essential for survival of intra-erythrocytic stages and is a valid target for drug development. A structural model of the 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 drug susceptibility assays. One compound, CB-27, exhibited antiplasmodial activity with an EC of 0.5 μM toward and 0.9 μM toward 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 EC 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.