Ensemble-based molecular docking and spectrofluorometric analysis of interaction between cytotoxin and tumor necrosis factor receptor 1

Misuan, Nurhamimah; Mohamad, Saharuddin Bin; Tubiana, Thibault; Yap, Michelle Khai Khun

doi:10.1080/07391102.2023.2188945

Cited by 4 publications

(4 citation statements)

References 72 publications

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“…This conserved CTX is highly matched to Naja atra cytotoxin (accession no: Q98959.1, Taiwan origin) with 95% sequence similarity 40 .…”

Section: Methodsmentioning

confidence: 97%

“…A conserved sequence of cytotoxin (CTX) was constructed in our laboratory 40 based on consensus sequence obtained from multiple sequence alignment of the non-redundant and mature CTX sequences (NCBI Serpentes protein database, Taxid: 8570). These sequences constitute different CTX isoforms of different Naja species 40 . The final consensus CTX sequence is shown below: …”

Section: Methodsmentioning

confidence: 99%

“…Therefore, in this study, epitope characteristics of CTXs were determined to identify the potential epitopes of significant relevance as synthetic epitope leads for next generation antivenoms. This study used a conserved CTX sequence deduced from various CTX isoforms from different Naja species, aiming to overcome the predicaments of species diversity and geographical variation 40 . We applied immunoinformatic and multi-enzymatic-limited-digestion/liquid chromatography-mass spectrometry (MELD/LC–MS) to determine the immunogenic properties of the conserved CTX can be determined.…”

Section: Introductionmentioning

confidence: 99%

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Unveiling the functional epitopes of cobra venom cytotoxin by immunoinformatics and epitope-omic analyses

Hiu

Fung

Tan

et al. 2023

Sci Rep

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Approximate 70% of cobra venom is composed of cytotoxin (CTX), which is responsible for the dermonecrotic symptoms of cobra envenomation. However, CTX is generally low in immunogenicity, and the antivenom is ineffective in attenuating its in vivo toxicity. Furthermore, little is known about its epitope properties for empirical antivenom therapy. This study aimed to determine the epitope sequences of CTX using the immunoinformatic analyses and epitope-omics profiling. A conserved CTX was used in this study to determine its T-cell and B-cell epitope sequences using immunoinformatic tools and molecular docking simulation with different Human Leukocyte Antigens (HLAs). The potential T-cell and B-cell epitopes were 'KLVPLFY,' 'CPAGKNLCY,' 'MFMVSTPTK,' and 'DVCPKNSLL.' Molecular docking simulations disclosed that the HLA-B62 supertype exhibited the greatest binding affinity towards cobra venom cytotoxin. The namely L7, G18, K19, N20, M25, K33, V43, C44, K46, N47, and S48 of CTX exhibited prominent intermolecular interactions with HLA-B62. The multi-enzymatic-limited-digestion/liquid chromatography-mass spectrometry (MELD/LC–MS) also revealed three potential epitope sequences as 'LVPLFYK,' 'MFMVS,' and ‘TVPVKR’. From different epitope mapping approaches, we concluded four potential epitope sites of CTX as ‘KLVPLFYK’, ‘AGKNL’, ‘MFMVSTPKVPV’ and ‘DVCPKNSLL’. Site-directed mutagenesis of these epitopes confirmed their locations at the functional loops of CTX. These epitope sequences are crucial to CTX’s structural folding and cytotoxicity. The results concluded the epitopes that resided within the functional loops constituted potential targets to fabricate synthetic epitopes for CTX-targeted antivenom production.

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“…This conserved CTX is highly matched to Naja atra cytotoxin (accession no: Q98959.1, Taiwan origin) with 95% sequence similarity 40 .…”

Section: Methodsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Unveiling the functional epitopes of cobra venom cytotoxin by immunoinformatics and epitope-omic analyses

Hiu

Fung

Tan

et al. 2023

Sci Rep

Self Cite

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show abstract

“…CTs are believed to target non-protein components of biological membranes [ 39 , 40 , 41 ]. An alternative viewpoint ascribing them capability to interact with some proteins, affecting their function, has not yet been supported experimentally [ 42 , 43 , 44 ]. The diversity of action targets makes toxins in the CT group extremely diverse in their effects on living cells, organs, and tissues [ 39 ].…”

Section: Ct Structure and Biological Effectsmentioning

confidence: 99%

Specific Amino Acid Residues in the Three Loops of Snake Cytotoxins Determine Their Membrane Activity and Provide a Rationale for a New Classification of These Toxins

Dubovskii,

Utkin

2024

Toxins

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Cytotoxins (CTs) are three-finger membrane-active toxins present mainly in cobra venom. Our analysis of the available CT amino acid sequences, literature data on their membrane activity, and conformational equilibria in aqueous solution and detergent micelles allowed us to identify specific amino acid residues which interfere with CT incorporation into membranes. They include Pro9, Ser28, and Asn/Asp45 within the N-terminal, central, and C-terminal loops, respectively. There is a hierarchy in the effect of these residues on membrane activity: Pro9 > Ser28 > Asn/Asp45. Taking into account all the possible combinations of special residues, we propose to divide CTs into eight groups. Group 1 includes toxins containing all of the above residues. Their representatives demonstrated the lowest membrane activity. Group 8 combines CTs that lack these residues. For the toxins from this group, the greatest membrane activity was observed. We predict that when solely membrane activity determines the cytotoxic effects, the activity of CTs from a group with a higher number should exceed that of CTs from a group with a lower number. This classification is supported by the available data on the cytotoxicity and membranotropic properties of CTs. We hypothesize that the special amino acid residues within the loops of the CT molecule may indicate their involvement in the interaction with non-lipid targets.

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Apoptotic Potential of Iloneoside from Gongronema latifolium Benth against Prostate Cancer Cells Using In Vitro and In Silico Approach

Gyebi,

Afolabi,

Ogunyemi

et al. 2024

Cell Biochem Biophys

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Prostate cancer is a major cause of cancer-related mortality in men worldwide. The anti-proliferative activity of Gongronema latifolium leaf extracts on some cancer cells has been reported. Herein, we investigated the growth inhibitory effect of the Gongronema latilolium leaf methanol extract and isolated pregnane (iloneoside) against prostate cancer cell lines using the MTT cell proliferation assay, apoptosis quantification, cell cycle analysis using flow cytometry and computational analysis molecular docking, molecular dynamics simulation (MDs), binding free energy computation and cluster analysis. In addition, UPLC-ESI-TOFMS chemical fingerprinting of previously isolated compounds was performed. The extract inhibited the growth of the cell lines with an IC50 of 49.3 µg/ml and 28.4 µg/ml for 24 h and 48 h, respectively, for PC3; and 43.7 µg/ml and 22.3 µg/ml for 24 h and 48 h, respectively, for DU145. Iloneoside demonstrated low inhibitory activities against PC3 and DU145 (IC50 > 80 μM). Apoptotic quantification and cell cycle analysis further showed that iloneoside induced apoptosis in a few cells at a dose of 200 uM. The ensemble-based molecular docking of the iloneoside to BCL-XL and BCL-2 proteins, and docking to MCL-1, BCL-A1 and BFL-1 proteins, respectively, presented binding energies of −7.22 ± 0.5, −8.12 ± 0.55, −7.1, −7.2 and −6.3 kcal/mol, while the MM/PBSA binding free energy was −25.72 ± 7.22 and −27.76 ± 11.32 kcal/mol for BCL-XL and BCL-2 proteins. Furthermore, iloneoside was stable during the 100 ns MDs analysis, while the clustering of the MDs trajectories showed that the interactions were strongly preserved. Iloneoside, in part, or in synergy with other constituents, may be responsible for the antiproliferative activities of the leaf, subject to further investigation.

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Ensemble-based molecular docking and spectrofluorometric analysis of interaction between cytotoxin and tumor necrosis factor receptor 1

Cited by 4 publications

References 72 publications

Unveiling the functional epitopes of cobra venom cytotoxin by immunoinformatics and epitope-omic analyses

Unveiling the functional epitopes of cobra venom cytotoxin by immunoinformatics and epitope-omic analyses

Specific Amino Acid Residues in the Three Loops of Snake Cytotoxins Determine Their Membrane Activity and Provide a Rationale for a New Classification of These Toxins

Apoptotic Potential of Iloneoside from Gongronema latifolium Benth against Prostate Cancer Cells Using In Vitro and In Silico Approach

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