Computational prediction and in vitro validation of VEGFR1 as a novel protein target for 2,3,7,8-tetrachlorodibenzo-p-dioxin

Chitrala, Kumaraswamy Naidu; Yang, Xiaoming; Busbee, Philip Brandon; Singh, Narendra P.; Bonati, Laura; Xing, Yongna; Nagarkatti, Prakash

doi:10.1038/s41598-019-43232-4

Cited by 7 publications

(5 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Molecular docking is a computational procedure that attempts to predict the non-covalent interactions of drug molecules (ligands) to larger macromolecules (target) [ 84 , 85 ]. The technique results in multiple leads that require experimental validation [ 86 , 87 , 88 ].…”

Section: Discussionmentioning

confidence: 99%

The Multistage Antimalarial Compound Calxinin Perturbates P. falciparum Ca2+ Homeostasis by Targeting a Unique Ion Channel

et al. 2022

View full text Add to dashboard Cite

Malaria elimination urgently needs novel antimalarial therapies that transcend resistance, toxicity, and high costs. Our multicentric international collaborative team focuses on developing multistage antimalarials that exhibit novel mechanisms of action. Here, we describe the design, synthesis, and evaluation of a novel multistage antimalarial compound, ‘Calxinin’. A compound that consists of hydroxyethylamine (HEA) and trifluoromethyl-benzyl-piperazine. Calxinin exhibits potent inhibitory activity in the nanomolar range against the asexual blood stages of drug-sensitive (3D7), multidrug-resistant (Dd2), artemisinin-resistant (IPC4912), and fresh Kenyan field isolated Plasmodium falciparum strains. Calxinin treatment resulted in diminished maturation of parasite sexual precursor cells (gametocytes) accompanied by distorted parasite morphology. Further, in vitro liver-stage testing with a mouse model showed reduced parasite load at an IC50 of 79 nM. A single dose (10 mg/kg) of Calxinin resulted in a 30% reduction in parasitemia in mice infected with a chloroquine-resistant strain of the rodent parasite P. berghei. The ex vivo ookinete inhibitory concentration within mosquito gut IC50 was 150 nM. Cellular in vitro toxicity assays in the primary and immortalized human cell lines did not show cytotoxicity. A computational protein target identification pipeline identified a putative P. falciparum membrane protein (Pf3D7_1313500) involved in parasite calcium (Ca2+) homeostasis as a potential Calxinin target. This highly conserved protein is related to the family of transient receptor potential cation channels (TRP-ML). Target validation experiments showed that exposure of parasitized RBCs (pRBCs) to Calxinin induces a rapid release of intracellular Ca2+ from pRBCs; leaving de-calcinated parasites trapped in RBCs. Overall, we demonstrated that Calxinin is a promising antimalarial lead compound with a novel mechanism of action and with potential therapeutic, prophylactic, and transmission-blocking properties against parasites resistant to current antimalarials.

show abstract

Section: Discussionmentioning

confidence: 99%

The Multistage Antimalarial Compound Calxinin Perturbates P. falciparum Ca2+ Homeostasis by Targeting a Unique Ion Channel

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Portulaca oleracea (duckweed) is an annual succulent in the Portulacaceae family with slight hogweed or parsley which may reach 16 inches in height [36]. Molecular docking permits rapid screening of the sequences of amino acid through many coronaviruses' species such as SARS-CoV-2 [23,37]. The reported docking data were promised and suggest a potential inhibition against the newly pandemic COVID-19 from the currently accessible natural plants [19].…”

Section: Research Articlementioning

confidence: 99%

“…The Docked complexes were subjected to 500 iterative cycles with a radius offset of 0.4, a gradient of 0.01, and one minimization cycle [40,41]. The inhibition constants and binding energy are recorded in each docking simulation [37]. The ligands were designated based on the computed binding scores [2].…”

Section: Molecular Docking Studymentioning

confidence: 99%

Investigating the Inhibition Effect of Portulaca oleracea against SARS-CoV-2 through Molecular Docking Simulation

AN¹,

EG²,

SM³

2021

austinjanalpharmchem

View full text Add to dashboard Cite

Recently a new virus strain designated as SARS coronavirus result in a fatal pandemic known as COVID-19. Bioinformatics and drug screening are directed for the assessment of potential inhibitors before their clinical implementation for the treatment of this fatal pneumonia. One of the expected natural potent inhibitors is Portulaca oleracea which has been assigned as an effective drug to different human ailments throughout the whole world. P. oleracea is widely spread in most areas of Egypt. In the current study, hydrophilic polysaccharides were purified from Portulaca oleracea extracts. Molecular docking simulation is implemented to investigate the antiviral effect of the purified polysaccharides to inhibit COVID-19. The viral protease was downloaded from a Protein Data Bank (PDB# 6y84) then docked with the potent inhibitors. The docking results indicate that the purified polysaccharides can bind tightly to the SARS-CoV-2 viral protease, which indicates that P. oleracea is a potential inhibitor for COVID-19.

show abstract

“…After model validation, alignment of the protein sequences, and subsequent molecular docking conducted to evaluate the antiviral effect of the previously reported drugs, and natural sources against SARS-CoV-2 protease. The binding energies and the inhibition constants are reported in each case [ 44 ]. All of the compounds were optimized in their active physiological settings [ 51 ].…”

Section: Materials and Reagentsmentioning

confidence: 99%

“…In this work, the author conducting a computational approach, through applying a combination of virtual screening, and molecular docking techniques, to assess the ability of some potential drugs, inhibitory ligands and natural products for the non-covalent inhibition of the SARS-CoV-2 main protease [ 40 ] through conformational and molecular docking studies. Molecular docking allows quick identification of the amino acid sequences across many coronaviruses including SARS-CoV-2 [ 7 , 44 ]. The obtained docking results were hopeful and proposed a potential inhibition against the newly emerged COVID-19 from the presently accessible therapeutics [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Investigating the potential antiviral activity drugs against SARS-CoV-2 by molecular docking simulation

El-hoshoudy

2020

Journal of Molecular Liquids

View full text Add to dashboard Cite

Recently, scary viral pneumonia is known as (COVID-19) has swept the whole world. The new virus strain designated as SARS-CoV-2 belonging to the coronavirus family. Although the current medical research directed towards the development of a novel therapeutic agent, no anti-viral drug approved until now. On the medical scale, the development of an approved drug is a time-consuming process, so research is directed towards screening of ligands and drugs multimodal structure-based-design and then docked to the main viral protease to investigate the active binding sites. The bioinformatic approaches used to evaluate the competence of a comprehensive range of ligands and drugs before their clinical implementation. In this study, a computational approach through molecular docking simulation is conducted for screening the antiviral activity of drugs, natural sources, and inhibitory compounds against the SARS-CoV-2 genome. The main virus protease was collected from a Protein Data Bank (PDB# 6YB7 ) and docked with a sequence of 19 approved antiviral drugs, 10 natural inhibitory ligands against COVID-19 downloaded from PubChem, in addition to 10 natural sources optimized for Escherichia coli BL 21 (DE 3 ) to identify the antiviral activity of these candidates against COVID-19. The docking results were promised and indicated that the reported ligands can firmly bind to the SARS-CoV-2 main protease and leads to inhibition of its infectious impact.

show abstract

Computational prediction and in vitro validation of VEGFR1 as a novel protein target for 2,3,7,8-tetrachlorodibenzo-p-dioxin

Cited by 7 publications

References 71 publications

The Multistage Antimalarial Compound Calxinin Perturbates P. falciparum Ca2+ Homeostasis by Targeting a Unique Ion Channel

The Multistage Antimalarial Compound Calxinin Perturbates P. falciparum Ca2+ Homeostasis by Targeting a Unique Ion Channel

Investigating the Inhibition Effect of Portulaca oleracea against SARS-CoV-2 through Molecular Docking Simulation

Investigating the potential antiviral activity drugs against SARS-CoV-2 by molecular docking simulation

Contact Info

Product

Resources

About