Targeting metacaspase-3 fromPlasmodium falciparumtowards antimalarial therapy: A combined approach ofin-silicoandin-vitroinvestigation

Kumar, Bhumika; Amaduddin,; Hussain, Afzal; Islam, Asimul; Ahmad, Faizan; Alajmi, Mohamed F.; Singh, Shailja; Pandey, Kailash C.; Hassan, Md. Imtaiyaz; Abid, Mohammad

doi:10.1080/07391102.2019.1711194

Cited by 6 publications

(4 citation statements)

References 26 publications

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“…The compactness of protein is another measure of computing the stability of protein molecules [ 34 ]. In MD simulations, the compactness measure is characterized as R g [ 35 ]. It is a useful parameter directly associated with the tertiary structure of a protein and has been widely employed in examining the compactness of a protein structure [ 36 , 37 ].…”

Section: Resultsmentioning

confidence: 99%

Structure-Guided Approach to Discover Tuberosin as a Potent Activator of Pyruvate Kinase M2, Targeting Cancer Therapy

Adnan

Shamsi

Elasbali

et al. 2022

IJMS

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Metabolic reprogramming is a key attribute of cancer progression. An altered expression of pyruvate kinase M2 (PKM2), a phosphotyrosine-binding protein is observed in many human cancers. PKM2 plays a vital role in metabolic reprogramming, transcription and cell cycle progression and thus is deliberated as an attractive target in anticancer drug development. The expression of PKM2 is essential for aerobic glycolysis and cell proliferation, especially in cancer cells, facilitating selective targeting of PKM2 in cell metabolism for cancer therapeutics. We have screened a virtual library of phytochemicals from the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) database of Indian medicinal plants to identify potential activators of PKM2. The initial screening was carried out for the physicochemical properties of the compounds, and then structure-based molecular docking was performed to select compounds based on their binding affinity towards PKM2. Subsequently, the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties, PAINS (Pan-assay interference compounds) patterns, and PASS evaluation were carried out to find more potent hits against PKM2. Here, Tuberosin was identified from the screening process bearing appreciable binding affinity toward the PKM2-binding pocket and showed a worthy set of drug-like properties. Finally, molecular dynamics simulation for 100 ns was performed, which showed decent stability of the protein-ligand complex and relatival conformational dynamics throughout the trajectory. The study suggests that modulating PKM2 with natural compounds is an attractive approach in treating human malignancy after required validation.

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Section: Resultsmentioning

confidence: 99%

Structure-Guided Approach to Discover Tuberosin as a Potent Activator of Pyruvate Kinase M2, Targeting Cancer Therapy

Adnan

Shamsi

Elasbali

et al. 2022

IJMS

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“… 36 Interestingly, Pv MCA1 ( Fig. 1 ; Cys427) and other metacaspases, including MCA1 of P. knowlesi and P. gallinaceum , present a second conserved cysteine adjacently preceding the consensus catalytic cysteine 11 , 14 and the involvement in proteolytic activity has been shown as well. 29 , 30 , 35 Notably, substitution of this alternative cysteine is not found in any of the P. vivax isolates analysed until now (Cys427), indicating by its high degree of conservation a possible role in Pv MCA1 activity.…”

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confidence: 88%

“…In this scenario, proteases playing significant roles in parasite survival have been for long time considered molecular targets for antimalarial drug development and, 9 , 10 more recently, members of metacaspase family, whose activity was already suggested to be implicated in both growth and cell death of Plasmodium and other protozoan parasites, have emerged as novel candidates. 11 , 12 Metacaspases are cysteine proteases belonging to the C14 family that are found in genome of protists, fungi, algae and plants. They present structural similarity to metazoan caspases, both having a conserved His-Cys catalytic dyad in the large (p20) domain, but different substrate specificity.…”

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confidence: 99%

Plasmodium vivax metacaspase 1 (PvMCA1) catalytic domain is conserved in field isolates from Brazilian Amazon

Souza

Escafa

Blanco

et al. 2021

Mem. Inst. Oswaldo Cruz

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In the present study, we investigated the genetic diversity of Plasmodium vivax metacaspase 1 ( Pv MCA1) catalytic domain in two municipalities of the main malaria hotspot in Brazil, i.e., the Juruá Valley, and observed complete sequence identity among all P. vivax field isolates and the Sal-1 reference strain. Analysis of Pv MCA1 catalytic domain in different P. vivax genomic sequences publicly available also revealed a high degree of conservation worldwide, with very few amino acid substitutions that were not related to putative histidine and cysteine catalytic residues, whose involvement with the active site of protease was herein predicted by molecular modeling. The genetic conservation presented by Pv MCA1 may contribute to its eligibility as a druggable target candidate in vivax malaria.

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“…Malaria is one of the endemic tropical parasitic diseases, caused by blood-borne Apicoplexan parasite P. falciparum especially in the developing world ( Aneja et al, 2016 ; Kumar et al, 2021 ). Irrespective of the efforts made to control malaria under its various eradication programs, in 2019, the World Health Organization (WHO) estimated 229 million cases of malaria worldwide and 409,000 deaths.…”

Section: Introductionmentioning

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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Targeting metacaspase-3 fromPlasmodium falciparumtowards antimalarial therapy: A combined approach ofin-silicoandin-vitroinvestigation

Cited by 6 publications

References 26 publications

Structure-Guided Approach to Discover Tuberosin as a Potent Activator of Pyruvate Kinase M2, Targeting Cancer Therapy

Structure-Guided Approach to Discover Tuberosin as a Potent Activator of Pyruvate Kinase M2, Targeting Cancer Therapy

Plasmodium vivax metacaspase 1 (PvMCA1) catalytic domain is conserved in field isolates from Brazilian Amazon

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

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