Modelling functional and structural impact of non-synonymous single nucleotide polymorphisms of the DQA1 gene of three Nigerian goat breeds

Yakubu, Abdulmojeed; Donato, Marcos De; Imumorin, Ikhide G.

doi:10.4314/sajas.v47i2.6

Cited by 10 publications

(9 citation statements)

References 33 publications

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“…A z-score of −8.0 was obtained, which showed that the modeled protein falls within the range of X-rays solved protein structures. A more negative z-score implies a better protein model [ 52 ]. The local model quality of the protein was also generated ( Figure 2 b).…”

Section: Resultsmentioning

confidence: 99%

In Silico Screening of Isocitrate Lyase for Novel Anti-Buruli Ulcer Natural Products Originating from Africa

et al. 2018

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Buruli ulcer (BU) is caused by Mycobacterium ulcerans and is predominant in both tropical and subtropical regions. The neglected debilitating disease is characterized by chronic necrotizing skin lesions attributed to a mycolactone, which is a macrolide toxin secreted by M. ulcerans. The preferred treatment is surgical excision of the lesions followed by a prolonged combination antibiotic therapy using existing drugs such as rifampicin and streptomycin or clarithromycin. These antibiotics appear not to be adequately potent and efficacious against persistent and late stage ulcers. In addition, emerging drug resistance to treatment poses great challenges. There is a need to identify novel natural product-derived lead compounds, which are potent and efficacious for the treatment of Buruli ulcer. Natural products present a rich diversity of chemical compounds with proven activity against various infectious diseases, and therefore, are considered in this study. This study sought to computationally predict natural product-derived lead compounds with the potential to be developed further into potent drugs with better therapeutic efficacy than the existing anti-buruli ulcer compounds. The three-dimensional (3D) structure of Isocitrate lyase (ICL) of Mycobacterium ulcerans was generated using homology modeling and was further scrutinized with molecular dynamics simulations. A library consisting of 885 compounds retrieved from the AfroDb database was virtually screened against the validated ICL model using AutoDock Vina. AfroDb is a compendium of “drug-like” and structurally diverse 3D structures of natural products originating from different geographical regions in Africa. The molecular docking with the ICL model was validated by computing a Receiver Operating Characteristic (ROC) curve with a reasonably good Area Under the Curve (AUC) value of 0.89375. Twenty hit compounds, which docked firmly within the active site pocket of the ICL receptor, were assessed via in silico bioactivity and pharmacological profiling. The three compounds, which emerged as potential novel leads, comprise ZINC38143792 (Euscaphic acid), ZINC95485880, and ZINC95486305 with reasonable binding energies (high affinity) of −8.6, −8.6, and −8.8 kcal/mol, respectively. Euscaphic acid has been reported to show minimal inhibition against a drug-sensitive strain of M. tuberculosis. The other two leads were both predicted to possess dermatological activity while one was antibacterial. The leads have shown promising results pertaining to efficacy, toxicity, pharmacokinetic, and safety. These leads can be experimentally characterized to assess their anti-mycobacterial activity and their scaffolds may serve as rich skeletons for developing anti-buruli ulcer drugs.

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Section: Resultsmentioning

confidence: 99%

In Silico Screening of Isocitrate Lyase for Novel Anti-Buruli Ulcer Natural Products Originating from Africa

et al. 2018

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“…The z-score of the unrefined model was − 7.32, while this parameter was − 7.36 after refining. The more negative z-score confirms improvement after the refinement of the three-dimensional structure of the vaccine [ 57 ].…”

Section: Discussionmentioning

confidence: 93%

In silico design of a multi-epitope vaccine against HPV16/18

et al. 2022

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Background Cervical cancer is the fourth most common cancer affecting women and is caused by human Papillomavirus (HPV) infections that are sexually transmitted. There are currently commercially available prophylactic vaccines that have been shown to protect vaccinated individuals against HPV infections, however, these vaccines have no therapeutic effects for those who are previously infected with the virus. The current study’s aim was to use immunoinformatics to develop a multi-epitope vaccine with therapeutic potential against cervical cancer. Results In this study, T-cell epitopes from E5 and E7 proteins of HPV16/18 were predicted. These epitopes were evaluated and chosen based on their antigenicity, allergenicity, toxicity, and induction of IFN-γ production (only in helper T lymphocytes). Then, the selected epitopes were sequentially linked by appropriate linkers. In addition, a C-terminal fragment of Mycobacterium tuberculosis heat shock protein 70 (HSP70) was used as an adjuvant for the vaccine construct. The physicochemical parameters of the vaccine construct were acceptable. Furthermore, the vaccine was soluble, highly antigenic, and non-allergenic. The vaccine’s 3D model was predicted, and the structural improvement after refinement was confirmed using the Ramachandran plot and ProSA-web. The vaccine’s B-cell epitopes were predicted. Molecular docking analysis showed that the vaccine's refined 3D model had a strong interaction with the Toll-like receptor 4. The structural stability of the vaccine construct was confirmed by molecular dynamics simulation. Codon adaptation was performed in order to achieve efficient vaccine expression in Escherichia coli strain K12 (E. coli). Subsequently, in silico cloning of the multi-epitope vaccine was conducted into pET-28a ( +) expression vector. Conclusions According to the results of bioinformatics analyses, the multi-epitope vaccine is structurally stable, as well as a non-allergic and non-toxic antigen. However, in vitro and in vivo studies are needed to validate the vaccine’s efficacy and safety. If satisfactory results are obtained from in vitro and in vivo studies, the vaccine designed in this study may be effective as a therapeutic vaccine against cervical cancer.

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“…The initial model had a z-score of − 2.46, whereas the refined model had a z-score of − 3.47. A more negative z-score indicates that the 3D refined model of the vaccine is of higher quality 75 . In the 3D refined model of the vaccine, 16 discontinuous B-cell epitopes were predicted.…”

Section: Discussionmentioning

confidence: 99%

Designing a novel multi‑epitope vaccine against Ebola virus using reverse vaccinology approach

Alizadeh

Amini‐Khoei

Tahmasebian

et al. 2022

Sci Rep

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Ebola virus (EBOV) is a dangerous zoonotic infectious disease. To date, more than 25 EBOV outbreaks have been documented, the majority of which have occurred in Central Africa. The rVSVG-ZEBOV-GP vaccine (ERVEBO), a live attenuated vaccine, has been approved by the US Food and Drug Administration (FDA) to combat EBOV. Because of the several drawbacks of live attenuated vaccines, multi-epitope vaccines probably appear to be safer than live attenuated vaccines. In this work, we employed immunoinformatics tools to design a multi-epitope vaccine against EBOV. We collected sequences of VP35, VP24, VP30, VP40, GP, and NP proteins from the NCBI database. T-cell and linear B-cell epitopes from target proteins were identified and tested for antigenicity, toxicity, allergenicity, and conservancy. The selected epitopes were then linked together in the vaccine's primary structure using appropriate linkers, and the 50S ribosomal L7/L12 (Locus RL7 MYCTU) sequence was added as an adjuvant to the vaccine construct's N-terminal. The physicochemical, antigenicity, and allergenicity parameters of the vaccine were all found to be satisfactory. The 3D model of the vaccine was predicted, refined, and validated. The vaccine construct had a stable and strong interaction with toll-like receptor 4 (TLR4) based on molecular docking and molecular dynamic simulation (MD) analysis. The results of codon optimization and in silico cloning revealed that the proposed vaccine was highly expressed in Escherichia coli (E. coli). The findings of this study are promising; however, experimental validations should be carried out to confirm these findings.

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Modelling functional and structural impact of non-synonymous single nucleotide polymorphisms of the DQA1 gene of three Nigerian goat breeds

Cited by 10 publications

References 33 publications

In Silico Screening of Isocitrate Lyase for Novel Anti-Buruli Ulcer Natural Products Originating from Africa

In Silico Screening of Isocitrate Lyase for Novel Anti-Buruli Ulcer Natural Products Originating from Africa

In silico design of a multi-epitope vaccine against HPV16/18

Designing a novel multi‑epitope vaccine against Ebola virus using reverse vaccinology approach

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