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

Abstract

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; EC50 = 2.8 µM) and chloroquine-resistant (RKL-9; EC50 = 6.7 µM) strains of Plasmodium falciparum. 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 Plasmodium berghei ANKA. No Evans blue staining in ST72 treatment indicated that ST72 mediated protection of blood–brain barrier integrity in mice infected with P. berghei. 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 in vitro and in vivo studies.

Evaluating Terrestrol A as an Inhibitor Against SARS‐CoV‐2and Invasive Fungal Pathogens: A Comprehensive Computational Analysis

“…As can be seen in Figure S32 (Supporting Information) there is either none or very minimal decrease (in case of 4K90, 6VSI and 7CR5) in intramolecular hydrogen bonding in complexes over the period of 50 ns. The PDF analysis also suggests constancy and does not show any significant change in intramolecular hydrogen bonding [114] …”

“…The PDF analysis also suggests constancy and does not show any significant change in intramolecular hydrogen bonding. [114] Overall, the MD simulations that were conducted revealed that the RMSD and RMSF values of the protein-ligand complexes indicated structural deviations and flexibility during the simulation. Despite an initial increase in RMSD upon binding with Terrestrol A(10), the complex remained stable throughout the entire simulation, rendering it an ideal system for further analysis.…”

Identification of Potential Antimalarial Drug Candidates Targeting Falcipain-2 Protein of Malaria Parasite—A Computational Strategy

“…A study by Rosmalena et al has shown that cinchona alkaloid derivatives have shown inhibitory action against FP-2 [ 41 ]. Uddin et al have also shown the inhibitory action of falcipain-2 against natural compounds [ 42 ]. In the present study, we have used 340 plant-derived alkaloids against FP-2 to identify the potential antimalarial agents.…”

In silico Evaluation of the Inhibitory Potential of Cymbopogonol from Cymbopogon citratus Towards Falcipain-2 (FP2) Cysteine Protease of Plasmodium falciparum

“…51 Previous works by different research groups have identified hits against FP2. 13,46,49,50 A molecular docking study was conducted and a similar binding pose of 3-(1-benzoyl-5-(4fluorophenyl)-4,5-dihydro-1H-pyrazol-3yl)-7-(diethylamino)-2Hchromen-2-one and epoxysuccinate in FP2 inhibition was observed. 13 Also, an in vitro validation study on the antiplasmodial activity of an acyl-hydrazone-based molecular hybrid against cysteine protease FP2 in silico was conducted.…”