RESUMEN
Chikungunya infection has been a cause of countless deaths worldwide. Due to lack of permanent treatment and prevention of this disease, the mortality rate remains very high. Therefore, we followed an immunoinformatics approach for the development of multi-epitope subunit vaccine which is able to elucidate humoral, cell-mediated and innate immune responses inside the host body. Both structural and non-structural proteins of chikungunya virus were utilized for prediction of B-cell and T-cell binding epitopes along with interferon-γ (IFN-γ) inducing epitopes. The vaccine construct is composed of ß-defensin as an adjuvant at the N-terminal followed by Cytotoxic T-Lymphocytes (CTL) and Helper T-Lymphocyte (HTL) epitopes. The same vaccine construct was also utilized for the prediction of B-cell binding epitopes and IFN-γ inducing epitopes. This was followed by the 3D model generation, refinement and validation of the vaccine construct. Later on, the interaction of modeled vaccine with the innate immune receptor (TLR-3) was explored by performing molecular docking and molecular dynamics simulation studies. Also to check the efficiency of expression of this vaccine construct in an expression vector, in silico cloning was performed at the final stage of vaccine development. Further, designed multi-epitope subunit vaccine necessitates experimental and clinical investigation to develop as an immunogenic vaccine candidate.
Asunto(s)
Virus Chikungunya/genética , Epítopos de Linfocito B/genética , Epítopos de Linfocito T/genética , Vacunas de Subunidad/genética , Vacunas Virales/genética , Animales , Antígenos Virales/química , Antígenos Virales/genética , Antígenos Virales/metabolismo , Fiebre Chikungunya/prevención & control , Fiebre Chikungunya/virología , Biología Computacional , Simulación por Computador , Epítopos de Linfocito B/química , Epítopos de Linfocito B/metabolismo , Epítopos de Linfocito T/química , Epítopos de Linfocito T/metabolismo , Genoma Viral/genética , Humanos , Ratones , Simulación de Dinámica Molecular , Vacunas de Subunidad/química , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/metabolismoRESUMEN
Malaria is an endemic disease caused by the protozoan parasite Plasomodium falciparum. Febrifugine analogues are natural compound obtained from the traditional Chinese herbs have shown significant antimalarial and anticancerous efficacy in experimental model. Development of resistance against the existing antimalarial drug has alarmed the scientific innovators to find a potential antimalarial molecule which can be further used by endemic countries for the elimination of this disease. In this study, structure-based virtual screening and molecular dynamics (MD) base approaches were used to generate potential antimalarial compound against plasmepsin II and prolyl-tRNA synthetase of Plasmodium. Here, we have docked series of febrifugine analogues (n = 11,395) against plasmepsin II in three different docking modes and then it was compared with previously reported target prolyl-tRNA synthetase. Extra precision docking resulted into 235 ligands having better docking score were subject for QikProp analysis. Better ligands (n = 39) obtained from QikProp analysis were subject for ADMET prediction and docking protocol validation through the estimation of receiver operator characteristics. In the later stage, 24 ligands obtained from ADMET study were subject for the estimation of binding energy through MM-GBSA and same were also docked against prolyl-tRNA synthetase to get compounds with dual inhibitor role. Finally, MD simulation and 2D fingerprint MACCS study of two best ligands have shown significant interaction with plasmepsin II and homology against known active ligand with noteworthy MACCS index, respectively. This study concludes that FA12 could be potential drug candidate to fight against Plasmodium falciparum parasites.
Asunto(s)
Aminoacil-ARNt Sintetasas/antagonistas & inhibidores , Antimaláricos/farmacología , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Simulación de Dinámica Molecular , Piperidinas/farmacología , Plasmodium falciparum/efectos de los fármacos , Proteínas Protozoarias/antagonistas & inhibidores , Quinazolinas/farmacología , Aminoacil-ARNt Sintetasas/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Conformación Molecular , Estructura Molecular , Unión Proteica , Proteínas Protozoarias/metabolismo , Relación Estructura-ActividadRESUMEN
Dengue is considered as a major health issue which causes a number of deaths worldwide each year; tropical countries are majorly affected by dengue outbreaks. It is considered as life threatening issue because, since many decades not a single effective approach for treatment and prevention of dengue has been developed. Therefore, to find new preventive measure, we used immunoinformatics approaches to develop a multi-epitope based subunit vaccine for dengue which can generate various immune responses inside the host. Different B-cell, TC cell, and TH cell binding epitopes were predicted for structural and non-structural proteins of dengue virus. Final vaccine constructs consisting of TC and TH cell epitopes and an adjuvant (ß-defensin) at N-terminal of the construct. Presence of B-cell and IFN-γ inducing epitopes confirms the humoral and cell mediated immune response developed by designed vaccine. Designed vaccine was not found allergic and was potentially antigenic in nature. Modeling of tertiary structure and the refined model was used for molecular docking with TLR-3 (immune receptor). Molecular docking and dynamics simulation confirms the microscopic interactions between ligand and receptor. In silico cloning approach was used to ensure the expression and translation efficiency of vaccine within an expression vector.