Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity

We employed a comprehensive approach of target-based virtual high-throughput screening to find potential hits from the ZINC database of natural compounds against cysteine proteases falcipain-2 and falcipain-3 (FP2 and FP3). Molecular docking studies showed the initial hits showing high binding affin...

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Published in:Frontiers in pharmacology 2022-04, Vol.13, p.850176-850176
Main Authors: Uddin, Amad, Gupta, Sonal, Mohammad, Taj, Shahi, Diksha, Hussain, Afzal, Alajmi, Mohamed F, El-Seedi, Hesham R, Hassan, Imtaiyaz, Singh, Shailja, Abid, Mohammad
Format: Article
Language:English
Subjects:
falcipain-2 inhibition
in vitro
in vivo
malaria
natural compounds
Pharmacology
virtual screening
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Summary:We employed a comprehensive approach of target-based virtual high-throughput screening to find potential hits from the ZINC database of natural compounds against cysteine proteases falcipain-2 and falcipain-3 (FP2 and FP3). Molecular docking studies showed the initial hits showing high binding affinity and specificity toward FP2 were selected. Furthermore, the enzyme inhibition and surface plasmon resonance assays were performed which resulted in a compound ZINC12900664 (ST72) with potent inhibitory effects on purified FP2. ST72 exhibited strong growth inhibition of chloroquine-sensitive (3D7; EC = 2.8 µM) and chloroquine-resistant (RKL-9; EC = 6.7 µM) strains of . Stage-specific inhibition assays revealed a delayed and growth defect during parasite growth and development in parasites treated with ST72. Furthermore, ST72 significantly reduced parasite load and increased host survival in a murine model infected with ANKA. No Evans blue staining in ST72 treatment indicated that ST72 mediated protection of blood-brain barrier integrity in mice infected with . ST72 did not show any significant hemolysis or cytotoxicity against human HepG2 cells suggesting a good safety profile. Importantly, ST72 with CQ resulted in improved growth inhibitory activity than individual drugs in both and studies.
ISSN:1663-9812
1663-9812
DOI:10.3389/fphar.2022.850176