Molecular dynamics simulations and biochemical characterization of <i>Pf</i>14-3-3 and <i>Pf</i>CDPK1 interaction towards its role in growth of human malaria parasite

Jain, Ravi; Dey, Pinki; Gupta, Sakshi; Pati, Soumya; Bhattacherjee, Arnab; Munde, Manoj; Singh, Shailja

doi:10.1042/bcj20200145

Cited by 13 publications

(9 citation statements)

References 111 publications

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“…Drug discovery approaches against falcipains as antimalarial targets look for stable and strong interaction of these proteins with small molecules of interest ( Kerr et al, 2009b ). Here, we employed SPR technique that monitors the binding of analytes with macromolecules in real time and gives quantitative response with good sensitivity ( Jain et al, 2020a ). Highest binding affinity of ST72 was observed for FP2 as compared to FP3 in the SPR study suggesting that ST72 is specific for cysteine protease FP2.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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“…This kind of molecule participates in the regulation of several cellular pathways [ 47 ]. The P. falciparum protein 14-3-3 (PF3D7_0818200) has been observed interacting with Pf CDPK1 and was proposed as a target for malaria treatment [ 48 ]. However, our primary and tertiary analyses for this protein show a high resemblance with the 14-3-3 orthologue in humans ( Figure 2 , Supplementary Table 3).…”

Section: Discussionmentioning

confidence: 99%

The search for molecular mimicry in proteins carried by extracellular vesicles secreted by cells infected with Plasmodium falciparum

Armijos-Jaramillo

Mosquera

Rojas

et al. 2021

Communicative & Integrative Biology

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Red blood cells infected with Plasmodium falciparum secrete extracellular vesicles in order to facilitate the survival and infection of human cells. Various researchers have studied the composition of these extracellular vesicles and identified the proteins contained inside. In this work, we used that information to detect potential P. falciparum molecules that could be imitating host proteins. We carried out several searches to detect sequences and structural similarities between the parasite and host. Additionally, the possibility of functional mimicry was explored in line with the potential role that each candidate can perform for the parasite inside the host. Lastly, we determined a set of eight sequences (mainly moonlighting proteins) with a remarkable resemblance to human proteins. Due to the resemblance observed, this study proposes the possibility that certain P. falciparum molecules carried by extracellular vesicles could be imitating human proteins to manipulate the host cell's physiology.

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“…2.5 mM DTT; 50 mM MgCl 2 and 2.5 mM MnCl 2 ), by following previously described protocols [41,59]. The enzymatic reaction was carried out in the absence and presence of calcium ions.…”

Section: In Vitro Kinase Assay With Rpfcdpk1 and Hepg2 Lysatementioning

confidence: 99%

“…The luminescence signal, thus generated, is proportional to the amount of ADP released in a given kinase reaction. Phosphorylation experiments were performed with 100 ng of 6xHis-CDPK1, per reaction, in assay buffer (100 mM Tris-Cl, pH 7.4; 2.5 mM DTT; 50 mM MgCl 2 and 2.5 mM MnCl 2 ), by following previously described protocols [41,59]. The enzymatic reaction was carried out in the absence and presence of calcium ions.…”

Section: Hemolytic Activitymentioning

confidence: 99%

Biological evaluation of novel side chain containing CQTrICh-analogs as antimalarials and their development as PfCDPK1 kinase inhibitors

Irfan¹,

Uddin

Jain

et al. 2022

Preprint

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To combat the emergence of drug resistance against the existing antimalarials, novel side chain containing 7-chloroquinoline-indole-chalcones tethered with a triazole (CQTrICh-analogs 7 (a-s) and 9) were designed and synthesized by reacting substituted 1-phenyl-3-(1-(prop-2-yn-1-yl)-1H-indol-3-yl) prop-2-en-1-one and 1-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde with 4-azido-7-chloroquinoline, respectively via a click reaction. The selected CQTrICh-analogs: 7l and 7r inhibited chloroquine-sensitive (3D7) and resistant (RKL-9) strains of Plasmodium falciparum, with IC50 values of 2.4 μM & 1.8 μM (7l), and 3.5 μM & 2.7 μM (7r), respectively, and showed insignificant hemolysis and cytotoxicity in mammalian cells. Intra-erythrocytic progression studies revealed that the active hybrids: 7l and 7r are effective against the mature stages of the parasite. Given the importance of Calcium-Dependent Protein Kinase 1 (PfCDPK1) in the parasite biology, notably during late schizogony and subsequent invasion of merozoites into host RBCs, we identified this protein as a possible molecular target of these active hybrids. In silico interaction analysis indicated that 7l and 7r stably interact with the catalytically active ATP-binding pocket of PfCDPK1, by the formation of energetically favorable H-bonds. Furthermore, in vitro Microscale Thermophoresis and kinase assays with recombinant PfCDPK1 demonstrated that the active hybrids interact with and inhibit the kinase activity, thus presumably responsible for the parasite growth inhibition. Interestingly, 7l and 7r showed no inhibitory effect on the human kinases, indicating that they are selective for the parasite kinase. Conceivably, we report the antiplasmodial potential of novel kinase targeting bio-conjugates, a step towards developing pan-kinase inhibitors, which is a prerequisite for cross-stage anti-malarial protection.

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Molecular dynamics simulations and biochemical characterization of Pf14-3-3 and PfCDPK1 interaction towards its role in growth of human malaria parasite

Cited by 13 publications

References 111 publications

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

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

The search for molecular mimicry in proteins carried by extracellular vesicles secreted by cells infected with Plasmodium falciparum

Biological evaluation of novel side chain containing CQTrICh-analogs as antimalarials and their development as PfCDPK1 kinase inhibitors

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