Three-dimensional models of antigens with serodiagnostic potential for leprosy:An in silico study

BACKGROUND Leprosy is a disease caused by Mycobacterium leprae(M.leprae),an intracellular pathogen that has tropism and affects skin and nervous system cells.The disease has two forms of presentation:Paucibacillary and multibacillary,with different clinical and immunological manifestations.Unlike what occurs in the multibacillary form,the diagnostic tests for the paucibacillary form are nonspecific and not very sensitive,allowing the existence of infected individuals without treatment,which contributes to the spread of the pathogen in the population.To mitigate this contamination,more sensitive diagnostic tests capable of detecting paucibacillary patients are needed.AIM To predict the three-dimensional structure models of M.leprae antigens with serodiagnostic potential for leprosy.METHODS In this in silico study,satisfactory templates were selected in the Protein Data Bank(PDB)using Basic Local Alignment Search Tool to predict the structural templates of ML2038,ML0286,ML0050,and 85B antigens by comparative modeling.The templates were selected according to general criteria such as sequence identity,coverage,X-ray resolution,Global Model Quality Estimate value and phylogenetic relationship;Clustal X 2.1 software was used in this analysis.Molecular modeling was completed using the software Modeller 9v13.Visualization of the models was made using ViewerLite 4.2 and PyMol software,and analysis of the quality of the predicted models was performed using the QMEAN score and Z-score.Finally,the three-dimensional moels were validated using the MolProbity and Verify 3D platforms.RESULTS The three-dimensional structure models of ML2038,ML0286,ML0050,and 85B antigens of M.leprae were predicted using the templates PDB:3UOI(90.51%identity),PDB:3EKL(87.46%identity),PDB:3FAV(40.00%identity),and PDB:1F0N(85.21%identity),respectively.The QMEAN and Z-score values indicated the good quality of the structure models.These data refer to the monomeric units of antigens,since some of these antigens have quaternary structure.The validation of the models was performed with the final three-dimensional structure-monomer(ML0050 and 85B antigens)and quaternary structures(ML2038 and ML0286).The majority of amino acid residues were observed in favorable and allowed regions in the Ramachandran plot,indicating correct positioning of the side chain and absence of steric impediment.The MolProbity score value and Verify 3D results of all models indicated a satisfactory prediction.CONCLUSION The polarized immune response against M.leprae creates a problem in leprosy detection.The selection of immunodominant epitopes is essential for the development of more sensitive serodiagnostic tests,for this it is important to know the three-dimensional structure of the antigens,which can be predicted with bioinformatics tools.

Decoding Retinoblastoma: Differential Gene Expression

Background: Retinoblastoma, the most common intraocular pediatric cancer, presents complexities in its genetic landscape that necessitate a deeper understanding for improved therapeutic interventions. This study leverages computational tools to dissect the differential gene expression profiles in retinoblastoma. Methods: Employing an in silico approach, we analyzed gene expression data from public repositories by applying rigorous statistical models, including limma and de seq 2, for identifying differentially expressed genes DEGs. Our findings were validated through cross-referencing with independent datasets and existing literature. We further employed functional annotation and pathway analysis to elucidate the biological significance of these DEGs. Results: Our computational analysis confirmed the dysregulation of key retinoblastoma-associated genes. In comparison to normal retinal tissue, RB1 exhibited a 2.5-fold increase in expression (adjusted p Conclusions: Our analysis reinforces the critical genetic alterations known in retinoblastoma and unveils new avenues for research into the disease’s molecular basis. The discovery of chemoresistance markers and immune-related genes opens potential pathways for personalized treatment strategies. The study’s outcomes emphasize the power of in silico analyses in unraveling complex cancer genomics.

Impact of Mutations on K-Ras-p120GAP Interaction

The K-Ras protein plays a key role in the signal transduction cascade. Certain mutations in K-Ras lead to a permanent “on” state which results in tumorigenesis due to failed interaction with the GTPase activating protein (GAP). In this study, we examined the mutations E31N, D33N and D38N of K-Ras coupled and decoupled to wildtype GAP-334 and mutation K935N of GAP-334 coupled and decoupled to wildtype K-Ras, to illustrate the potential mechanism by which these mutants affect the interaction between the two proteins. We identify Tyr32 in the Ras Switch I region as a critical residue that acts as a gate to the GTP binding site and which needs to be “open” during Ras coupling with GAP to allow for insertion of GAP residue Arg789. This residue plays a vital role in stabilizing the transition state during GTP hydrolysis. The different mutations studied herein caused a reduced binding affinity, and the fluctuation of the Tyr32 side chain might hinder the insertion of Arg789. This may in turn be the cause of decreased GTP hydrolysis, and permanent “on” state of K-Ras, observed for these mutants.

Microwave assisted synthesis and in silico screening of steroidal pyrazolines

The present manuscript describes solid-state synthesis of some reported steroidal pyrazolines by a novel eco-friendly route. The synthesized pyrazolines were compared with those obtained from conventional methods in terms of reaction time and overall yield. A substantial enhancement in reaction rate and yield was observed. The antimicrobial activity and the subsequent molecular docking studies of the steroidal pyrazolines have also been carried out.

Synthesis, in vitro antitumor activity and molecular modeling studies of a new series of benzothiazole Schiff bases

A new series of benzothiazole Schiff bases 3–29 was synthesized and screened for antitumor activity against cervical cancer（Hela） and kidney fibroblast cancer（COS-7） cell lines. Results indicated that compounds 3, 14, 19, 27 and 28 have promising activity against Hela cell line with IC50 values of 2.41,3.06, 6.46, 2.22 and 6.25 mmol/L, respectively, in comparison to doxorubicin as a reference antitumor agent（IC50 2.05 mmol/L）. In addition, compound 3 displayed excellent activity against COS-7 cell line with IC50 value of 4.31 mmol/L in comparison to doxorubicin（IC50 3.04 mmol/L）. In the present work,structure based pharmacophore mapping, molecular docking, protein-ligand interaction, fingerprints and binding energy calculations were employed in a virtual screening strategy to identify the interaction between the compounds and the active site of the putative target, EGFR tyrosine kinase. Molecular properties, toxicity, drug-likeness, and drug score profiles of compounds 3, 14, 19, 27, 28 and 29 were also assessed.